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Anticancer Agents Med Chem. 2013 September ; 13(7): 988–994.

Hitting the Golden TORget: Curcumin’s Effects on mTOR

Signaling
Christopher S. Beevers1,*, Hongyu Zhou2, and Shile Huang3,4,*
1Department of Pharmacology, Ross University School of Medicine, Picard-Portsmouth,

Commonwealth of Dominica, West Indies

2Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Kunming,
Yunnan Province, 650201, People’s Republic of China
3Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences
Center, Shreveport, Louisiana, USA
4Feist-Weiller
Cancer Center, Louisiana State University Health Sciences Center, Shreveport,
Louisiana, USA
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Abstract
The polyphenol natural product curcumin possesses a plethora of biological and pharmacological
properties. For years, much interest has been placed in the development and use of curcumin and
its derivatives for the prevention and treatment of cardiovascular, diabetic, and neurodegenerative
diseases, as well as cancer. Increasing evidence suggests that curcumin displays amazing
molecular versatility, and the number of its proposed cellular targets grows as the research
continues. The mammalian target of rapamycin (mTOR) is a master kinase, regulating cell growth/
proliferation, survival, and motility. Dysregulated mTOR signaling occurs frequently in cancer,
and targeting mTOR signaling is a promising strategy for cancer therapy. Recent studies have
identified mTOR as a novel target of curcumin. Here we focus on reviewing current knowledge
regarding the effects of curcumin on mTOR signaling for better understanding the anticancer
mechanism of curcumin. The emerging studies of mTOR signaling and clinical studies on
curcumin with cancer patients are also discussed here.

Keywords
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Curcumin; mTOR; Akt; Cancer; Cell proliferation; Cell death

1. Curcumin
Phytochemicals are plant-based molecules that are non-nutritive in nature, but possess
beneficial pharmacological actions in the human body when ingested [1]. Over the past
decades, interest in the potential use of phytochemicals as chemopreventive and
chemotherapeutic agents has grown both scientifically and publically, with the greatest
amount of attention being paid to their potential application in the fight against
cardiovascular disease and cancer [1]. Turmeric, a spice produced from the rhizome of the
perennial Asian herb Curcuma longa, has been especially popular in this growing interest in

*
Correspondence to: Christopher S. Beevers, Ph.D., Department of Pharmacology, Ross University School of Medicine, 630 US Hwy
1, North Brunswick, NJ 08902, USA. Phone: +1-767-255-6368; Fax: +1-767-445-5897; [email protected]; Shile Huang,
Ph.D., Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway,
Shreveport, LA 71130-3932, USA. Phone: +1-318-675-7759; Fax: +1-318-675-5180; [email protected].
 Beevers et al. Page 2

botanical pharmacology, owing to its distinguished and long history as a therapeutic agent in
Oriental medicine for several thousand years. In this capacity, turmeric has been utilized
topically for the treatment of open wounds, skin tumors, and inflammatory conditions, while
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orally ingested forms have been used to remedy gastrointestinal disorders and other internal
ailments [1, 2].

Analyses of turmeric have identified its major chemical constituents as a family of

polyphenolic compounds called the curcuminoids, which include curcumin [1,7-bis-(4-
hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], curcumin II (demethoxycurcumin),
and curcumin III (bis-demethoxycurcumin) [1, 2]. Curcumin is the most biomedically potent
chemical component in turmeric, and it comprises approximately 2–8% of most turmeric
preparations [1, 2]. Hundreds of scientific studies conducted over the past 30 years have
extensively studied the chemical, biochemical, pharmacological, and clinical properties of
curcumin [1, 2]. The vast majority of these investigations have specifically attempted to
elucidate the potential chemopreventive and chemotherapeutic value of this phytochemical
in the battle against human diseases, particularly neurodegenerative disorders, inflammatory
conditions, gastrointestinal disorders, cardiovascular diseases, and cancer [1, 2].

Curcumin (molecular weight: 368.37) possesses a conjugated double bond heptadienone

linker containing a bis-α,β-unsaturated β-diketone moiety [1]. This linker joins together the
molecule’s two methoxyphenol rings [1]. The diketone moiety undergoes tautomerization in
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a pH-dependent fashion [1]. The bis-keto tautomer displays potent Brønsted acid activity,
while the enol tautomer functions as a powerful Lewis Base [3]. Curcumin is insoluble in
water, but is soluble in organic solvents such as acetone, ethanol, and dimethylsulfoxide
(DMSO) [2]. In neutral/alkaline solutions the compound displays a dark red color, while in
acidic solutions it adopts a vibrant yellow color [2]. Curcumin is extremely unstable in
phosphate-based buffers, normal cell culture media, and most alkaline solutions, while it is
extremely stable in acidic solutions [1, 2, 4].

A number of clinical trials have addressed the safety and pharmacokinetics of curcumin in
humans. The safety and tolerability of curcumin at high doses are well established [5–7]. In
patients with high-risk or pre-malignant lesions, oral dose ranging from 500 to 8000 mg/day
for 3 months are well tolerated [6]. However, the in vivo bioavailability of curcumin is poor,
due to a combination of efficient first pass metabolism, poor gastrointestinal absorption,
rapid elimination, and poor aqueous solubility [8, 9]. After oral dosing, curcumin is
metabolized into several chemical species, including curcumin glucuronide, curcumin
sulfate, hexahydrocurcumin, tetrahydrocurcumin, and dihydrocurcumin [10]. One of the
current major initiatives in the field of curcumin study has been the manipulation and
optimization of the compound’s pharmacokinetic characteristics via the development of
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curcumin derivatives and curcumin-drug vehicle combinations that display greatly enhanced
absorption and systemic bioavailability, and many of these studies appear to be very
promising [10, 11].

Without question, the most intensive study of curcumin has been exploration of its
pharmacodynamic profiles, namely its mechanisms of action, pharmacological actions, and
pharmacological effects, and how these profiles are potentially translated into clinical use
and responsiveness. Those studies have been carried out extensively in vitro (human cell
lines) and in vivo (both animals and humans), and have been thoroughly reviewed [1, 2, 9,
10, 12, 13]. Consistent with the strong pre-clinical evidence of its pharmacological
activities, curcumin has been in early clinical trials for treatment of a variety of human
diseases, including rheumatoid arthritis [14, 15], ulcerative colitis, Alzheimer’s disease [15],
multiple myeloma [15], pancreatic cancer [15, 16], and colon cancer [2, 15]. Here we only
focus on reviewing some clinical trials related to cancer.

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A phase I study evaluated the toxicology, pharmacokinetics, and biologically effective dose
of curcumin in 25 patients with various types of high-risk or pre-malignant lesions [6]. After
an initial dose of 0.5 g curcumin daily, the dose was increased to as much as 8 g daily for 3
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months. There was no treatment-related toxicity up to 8 g/day. Histological improvement of

precancerous lesions was observed in 1 of 2 patients with recently resected bladder cancer
(decreased dysplasia and inflammation), 1 of 6 patients with intestinal metaplasia of the
stomach (fewer goblet cells), 1 of 4 patients with cervical intraepithelial neoplasm
(decreases in hyperkeratosis, parakeratosis), 2 of 7 patients with oral leukoplakia, and 2 of 6
patients with Bowen’s disease, indicating a biologic effect of curcumin in the
chemoprevention of cancer [6].

Two clinical phase I dose-escalation studies have investigated the use of curcumin therapy
in patients with advanced colorectal cancer [7, 17]. In the pilot study, 15 patients received an
oral capsule of Curcuma extract at doses between 440 and 2,200 mg/day, containing 36–180
mg of curcumin, for up to 4 months [7]. The compound was well tolerated, and dose-
limiting toxicity was not observed. The lymphocytic biomarker glutathione S-transferase
(GST) activity showed a 59% decrease with ingestion of low-dose (440 mg/day) of curcuma
extract, and radiologically stable disease was demonstrated in 5 patients for 2–4 months of
the study period [7]. In a subsequent study in a similar population, Sharma et al. further
explored the pharmacology of curcumin administered in capsules compatible with curcumin
doses between 0.45 and 3.6 g/day for up to 4 months [17]. Three biomarkers of the potential
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activity of curcumin were measured in patient blood leukocytes: GST activity, levels of
deoxyguanosine adduct M(1)G, and PGE2 production induced ex vivo. In blood samples
taken 1 h after the dose on Days 1 and 29, consumption of 3.6 g of curcumin daily decreases
inducible PGE2 production by 62% and 57%, respectively, when compared with levels
observed immediately before administering the drug [17]. Consequently, the 3.6 g dose was
chosen for further evaluation in phase II trial in cancers outside the gastrointestinal tract
[17].

In another clinical trial, 25 patients with advanced pancreatic cancer received 8 g curcumin
orally every day, and 21 of them exhibited evaluable responses [16]. Of note, one patient
achieved disease stabilization for 18 months, and another patient had a brief, but marked,
tumor regression (73%) accompanied by 4- to 35-fold increases in serum cytokine levels
(IL-6, IL-8, IL-10 and IL-1 receptor antagonists) [16]. Downregulated expression of NF-κB,
COX-2, and phosphorylated signal transducer and activator of transcription 3 (Stat3) by
curcumin in peripheral blood mononuclear cells from patients were also observed [16]. In an
interesting, but uncontrolled study of 62 patients with oral cancerous lesions, topical
curcumin application produced remarkable symptomatic relief in patients. Dry lesions were
noted in 70% of the cases, and a reduction in lesion size and pain was observed in 10% of
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patients [18]. Currently, a search on the web of http://clinicaltrials.gov shows that there are
17 clinical trials investigating the preventive or therapeutic efficacy of curcumin in cancer
patients. Five studies have completed, and 12 are ongoing. Hopefully, these ongoing trials
over the next few years will provide a better understanding of the anticancer potential of
curcumin in patients with different cancers.

Preclinical studies in cell culture and in animal models strongly support that curcumin has
the ability to exert anti-cancer actions, including inhibiting cell proliferation/growth and
motility [2, 13, 19], inducing cell death and inhibiting angiogenesis [2, 13, 19, 20]. These
studies also suggest that curcumin possesses amazing molecular versatility as evidenced by
the large number of proposed drug receptors for the compound, including plasma
membrane-bound receptors, proteases, transporters, apoptotic factors, kinases, transcription
factors, and adhesion molecules [2, 12]. While it remains a possibility that curcumin is in
fact interacting with this seemingly large range of molecules, a more plausible explanation is

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that curcumin predominately targets only a few key cell regulators, and these actions spill
over to affect many different pathways, factors, and processes within the cell. Identifying
these key cellular regulators, however, remains challenging due to the seemingly diverse
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molecular promiscuity of the compound. Recently, the mammalian target of rapamycin

(mTOR) has been identified as a novel molecular target of curcumin, which may in fact
represent one of these central targets due to the fact that mTOR stands at the center of
numerous key cellular processes (cell growth/proliferation, survival and motility), almost all
of which are affected to some degree by curcumin.

2. mTOR
The serine/threonine protein kinase mTOR is composed of 2549 amino acids and has a
molecular mass of 289 kDa [21]. Numerous studies demonstrated that cellular conditions
that are sufficient to suppress in vivo mTOR kinase activity do not affect the in vitro kinase
activity of purified mTOR [21, 22]. This led to the conclusion that mTOR functions in vivo
as the catalytic subunit of one or more supramolecular protein complexes that control the
intrinsic kinase activity of mTOR [23]. Subsequent studies have confirmed this original
hypothesis to be true and so far have identified at least two such complexes (Fig. 1): mTOR
complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [24].

mTOR lies downstream of numerous cell surface receptors, including the insulin receptor,
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the insulin-like growth factor type 1 receptor (IGF-1R), the epidermal growth factor
receptor, and many others [20, 25–27]. Activation of these receptors stimulates the activity
of phosphatidylinositol 3-kinase (PI3K) which facilitates the events necessary for the plasma
membrane association and initiation of activation of the serine/threonine protein kinase Akt/
protein kinase B (Akt/PKB) [28, 29] (Fig. 1). Upon association with the plasma membrane,
Akt undergoes two key stimulatory phosphorylation events [30]. The most important of
these occurs at Ser473 by the action of mTORC2, which is composed of mTOR, rapamycin
insensitive companion of mTOR (Rictor), G-protein β-subunit like protein (GβL),
mammalian Sin1 (mSin1), protein observed with Rictor-1 and -2 (protor-1 and protor-2),
and DEP domain containing mTOR-interactiong protein (DEPTOR) [31–33] (Fig. 1).
Following this event and other activating modifications, Akt undergoes full activation and
can phosphorylate a large number of cellular targets. One of these is the tuberous sclerosis
complex 2 (TSC2) [25]. Akt phosphorylates TSC2 at several locations [25, 34, 35],
inhibiting TSC2 GTPase activating protein (GAP) activity on the small GTPase ras homolog
enriched in brain (Rheb) [25, 35]. Once Rheb is locked in the bound-guanosine triphosphate
(GTP) state, it becomes active and in turn activates mTORC1 through direct binding and
stimulation of its kinase activity [25, 35–37].
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mTORC1 is composed of mTOR, regulatory associated protein of mTOR (Raptor), GβL,

proline-rich Akt1 substrate of 40 kDa (PRAS40) and DEPTOR [23, 25, 38, 39]. mTORC1
signals to two primary downstream targets, p70 S6 kinase 1 (S6K1) and eukaryotic
translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) [25] (Fig. 1). S6K1 is a
serine/threonine protein kinase that is involved in regulation of cell growth and G1 cell cycle
progression [40, 41]. S6K1 undergoes several activating phosphorylation events, including
mTORC1-mediated phosphorylation of Thr389 [41], an event that correlates best with S6K1
activity [42]. Activated S6K1 was originally thought to regulate protein synthesis through
phosphorylation of the 40S ribosomal subunit, which has been suggested to increase the
translational efficiency of a class of mRNA transcripts with a 5′-terminal
oligopolypyrimidine sequence [43]. Recently, it has been further proposed that the
mechanism by which S6K1 regulates translation is likely by phosphorylation of eIF4B at
Ser422 [44], which causes it to associate with eIF3 and promotes eIF4F complex formation
[45, 46]. 4E-BP1 binds eIF4E, preventing it from participating in cap-dependent translation

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initiation [47]. Phosphorylation of 4E-BP1 by mTORC1 stimulates protein synthesis through

the release of eIF4E from 4E-BP1, allowing eIF4E to associate with eIF4G and other
relevant factors to promote cap-dependent translation [47, 48].
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mTOR truly functions as a master cellular regulator. It acts as a sensor of growth factor
stimuli [25], nutrient [23, 49], energy [49], redox [50], and oxygen levels [51, 52] (Fig. 1).
mTOR controls numerous cellular processes such as cell proliferation [53], cell growth
(size) [23, 54], cell motility [55], cell survival [56, 57], and metabolism [53]. In humans,
dysregulated mTOR signaling is implicated in a wide range of disease processes [53, 58,
59], including tuberous sclerosis [53, 60], diabetes [61, 62], obesity [62],
lymphangiomyelomatosis [63], and most types of cancer [58, 62, 64, 65]. mTORC1 and
mTORC2 are essential complexes, as downregulation of Raptor, Rictor, and mSin1 leads to
embryonic lethality [66, 67]. mTORC1 regulates, to varying degrees, transcription [53, 68,
69], translation initiation [25, 48], nutrient transport [56, 70], autophagy [71–73], and
ribosome biogenesis [74, 75]. mTORC2 controls actin cytoskeleton organization, cell shape
[76, 77], and cell motility via its effects on the Rho-type GTPases [76], focal adhesion
proteins, and protein kinase C (PKC) [77]. mTORC2 also regulates cell survival via
activation of Akt and serum- and glucocorticoid-inducible kinase 1 (SGK1) [32, 78] and the
subsequent regulation of its numerous cellular targets, including the Foxo family of
transcription factors [79] and the apoptosis-regulating Bcl-2 family of proteins such as BAD
[80].
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3. Curcumin and mTOR: The Golden Couple

The worlds of curcumin and mTOR first collided in studies conducted in
rhabdomyosarcoma (RMS) cell lines [20]. Curcumin inhibited proliferation and induced
apoptosis of RMS cells in a concentration-dependent manner (2.5–40 μM) [20]. Curcumin
inhibition of cell proliferation was related to the arrest of cells in the G1/G0 phase of the cell
cycle [20]. Curcumin also blocked the basal and IGF-1-stimulated cell motility of these
RMS cells [20]. It has been well documented that RMS is a type of cancer that possesses as
one of its major genetic/molecular features the upregulation and dysregulation of the
IGF-1R/PI3K/Akt/mTOR signal transduction cascade [20, 55, 81]. Of note, rapamycin, the
first identified inhibitor of mTORC1 signaling, successfully inhibits the proliferation/
growth, motility, and survival of RMS cells [55, 57, 82, 83]. This information drove the
authors to investigate whether or not curcumin might be acting on some component of the
IGF-1R/PI3K/Akt/mTOR pathway. Subsequent experiments demonstrated that curcumin
inhibited the IGF-1-stimulated, mTORC1-mediated phosphorylation of S6K1 and 4E-BP1 at
low concentrations (~2.5 μM), and the IGF-1-stimulated, mTORC2-mediated
phosphorylation of Akt at higher concentrations (>40 μM) in RMS cells [20]. Similar results
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were also observed in prostate (DU145), breast (MCF-7), and cervical (HeLa) cancer cell
lines [20].

Upon the publication of these results, numerous other investigations began confirming the
interaction of curcumin with the mTOR pathway. Curcumin treatment of human prostate
cancer cells (PC3) lead to a dose- and time-dependent decrease in the transcriptional
expression of the p53 ubiquitin E2 ligase murine double minute 2 (MDM2), and this was
mediated via curcumin action on the PI3K/mTOR/ETS2 pathway [84]. Curcumin induced
G2/M cell cycle arrest and autophagy in two human malignant glioma cell lines (U87-MG
and U373-MG) [85]. These effects were related to curcumin inhibition of mTORC2 (as
indicated by the phosphorylation of Akt) and activation of the ERK pathway, as
reconstitution of Akt activity and inhibition of ERK (use of PD98059) prevented curcumin-
mediated autophagy [85]. Curcumin treatment also prevented growth of these tumor cells in
vivo by inducing autophagy [85]. Curcumin was able to decrease the transcriptional and

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translational expression of mTOR, Raptor, and Rictor in human colorectal cancer cells
(HCT116) [86]. Lim et al. suggested that curcumin-mediated inhibition of mTOR signaling
could be the result of its function as a protonophoric uncoupler and activator of F0F1-
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ATPase, thus leading to 5′-AMP-activated protein kinase (AMPK) activation and its
induction of mTOR inhibition [87]. Curcumin was able to attenuate irradiation-mediated
activation of Akt and mTOR phosphorylation in human intestinal microvascular endothelial
cells and this correlated with curcumin-mediated induction of apoptosis [88]. The compound
was able to block basal and nicotine-stimulated mTORC1 signaling in human head and neck
squamous cell carcinoma cell lines (PCI15a and SCC40) and this correlated with inhibition
of cell proliferation, invasion, and migration [89]. A study conducted in adenoid cystic
carcinoma cells suggested that curcumin inhibitory action on both mTOR signaling and the
NF-κB pathway may be related to crosstalk via the PI3K/Akt/IκB kinase network [90].
Curcumin was able to inhibit mTORC1 signaling in autosomal dominant polycystic kidney
disease, even in the presence of a deletion of the gene encoding polycystin-1 (PC1), a
molecular genotype that results in an activated mTOR pathway phenotype [91]. Curcumin
also inhibited mTORC1 signaling in human leiomyosarcoma cells (SKN), an event that was
correlated with decreased cell growth/proliferation and induction of apoptosis [92], and this
activity of curcumin was enhanced when it was administered in combination with
epigallocatechin-3-gallate (EGCG) [93]. The compound also successfully abrogated
mTORC1 signaling in squamous cell carcinoma cells in vivo [94]. Curcumin, as well as
rapamycin and several other compounds, successfully enhanced the efficiency of
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reprogramming somatic cells into induced pluripotent stem cells, more than likely via
inhibition of the IGF-1/mTOR signaling pathway [95].

To date, at least two major studies [26, 96] have been undertaken to determine the
mechanism of action by which curcumin disrupts mTORC1 and mTORC2 signaling. The
first was conducted by Yu et al. utilizing human prostate cancer cells (PC3) [96]. This study
demonstrated that curcumin inhibited the mTORC2- and PDK1-mediated phosphorylation
of Akt and the mTORC1-mediated phosphorylation of S6K1 and 4E-BP1 at similar
concentrations [96]. This study also found that curcumin stimulated the phosphorylation and
activity of AMPK, which serves as a positive regulator of TSC2 [96]. Use of a PI3K-rescue
agent and a phosphatidylinositol-dependent kinase 1 (PDK1) in vitro kinase assay revealed
that curcumin action on the complexes of mTOR was independent of PI3K and PDK1, while
overexpression of Akt did not prevent curcumin inhibition of mTORC1-mediated S6K1 and
4E-BP1 phosphorylation [96]. Overexpression of wild-type and dominant-negative AMPK
and pretreatment of cells with the AMPK inhibitor compound C did not block curcumin
abrogation of mTORC1-mediated phosphorylation of its two major downstream targets [96].
Genetic and siRNA knockdown of TSC2 also failed to interfere with curcumin-mediated
inhibition of mTORC1 activity [96]. Finally, use of the serine/threonine protein phosphatase
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inhibitors calyculin A and okadaic acid was able to reverse curcumin inhibition of both
mTORC1 and mTORC2 signaling, suggesting that curcumin might be acting directly as an
activator of protein phosphatase 2A (PP2A), thus leading to inhibition of the mTOR
pathway [96]. This is indeed a possibility because PP2A functions as the major phosphatase
responsible for the dephosphorylation of the mTORC1 substrates S6K1 [97, 98] and 4E-BP1
[99], and the mTORC2 substrate Akt [97, 100].

The second study was carried out primarily in RMS cells by Beevers et al. [26]. This study
also showed that the IGF-1R, the PDK1, and the AMPK/TSC2 pathways did not play a role
in curcumin-mediated inhibition of mTORC1 and mTORC2 signaling [26]. However, PP2A
was found not to be involved in curcumin action on the mTOR pathway, as the use of
okadaic acid, expression of dominant-negative PP2A, and shRNA-mediated downregulation
of PP2A was unable to prevent curcumin inhibition of mTORC1 and mTORC2 signaling in
rhabdomyosarcoma cells [26]. Whether the discrepancy between the studies [26, 96] is

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related to different cell lines or experimental conditions used remains to be defined. Of

interest, Beevers et al. observed that low concentrations of curcumin (2.5 μM) blocked the
kinase activity of the mTORC1 by disrupting mTOR-Raptor interaction and that higher
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concentrations of the compound (40 μM) inhibited the kinase activity of the mTORC2 by
disrupting mTOR-Rictor interaction [26]. This concentration-dependent effect of curcumin
on the two complexes of mTOR fits data concerning the nature of the two complexes. The
interaction of mTOR with Raptor in the mTORC1 is a weak and dynamic association,
facilitating the large amount of control that is needed over mTORC1 activity [23], while the
mTOR-Rictor interaction in the mTORC2 appears to be a much stronger and more static
association [77]. At that time (2008), these results suggested that curcumin was the first, and
currently only, identified compound to exert activity against both complexes of mTOR
specifically by disrupting complex partner interactions.

4. Conclusions
mTOR is a master kinase that controls cell proliferation/growth, survival, and motility. Over
the past 6 years, mTOR has emerged as an exciting and novel molecular target for curcumin,
particularly in cancer cell lines. It appears that curcumin inhibits both mTORC1 and
mTORC2, but in a concentration-dependent manner. There exist some discrepant findings
regarding the mechanism by which curcumin inhibits mTOR signaling pathways. The
findings have opened the doors to many different avenues of research into the interactions
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between curcumin and mTOR and the cellular processes and factors affected by this
interaction. Obviously, much work remains to be done, including identifying the exact
mechanism by which curcumin disrupts mTOR activity and complex formation/stability and
whether or not these results can translate over into other disease states and/or normal human
tissue as well. Obviously, the ultimate aim of these molecular studies would be to attempt to
replicate these discoveries within in vivo cancer models in animals. Greater demonstration
of successful replication of these results in animal models may provide the necessary
stimulus to induce the initiation of clinical trials in humans using various formulations/
derivatives of curcumin as chemotherapeutic and/or chemopreventive agents against many
types of cancer.

Acknowledgments
This work was supported in part by NIH (CA115414 to S. Huang), and American Cancer Society (RSG-08-135-01-
CNE to S. Huang).

References
1. Sharma RA, Gescher AJ, Steward WP. Curcumin: the story so far. Eur J Cancer. 2005; 41:1955–
NIH-PA Author Manuscript

1968. [PubMed: 16081279]

2. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical
studies. Anticancer Res. 2003; 23:363–398. [PubMed: 12680238]
3. Jovanovic SV, Boone CW, Steenken S, Trinoga M, Kaskey RB. How curcumin works preferentially
with water soluble antioxidants. J Am Chem Soc. 2001; 123:3064–3068. [PubMed: 11457017]
4. Tonnesen HH, Karlsen J. Studies on curcumin and curcuminoids. VI. Kinetics of curcumin
degradation in aqueous solution. Z Lebensm Unters Forsch. 1985; 180:402–404. [PubMed:
4013525]
5. Shankar TN, Shantha NV, Ramesh HP, Murthy IA, Murthy VS. Toxicity studies on turmeric
(Curcuma longa): acute toxicity studies in rats, guineapigs & monkeys. Indian J Exp Biol. 1980;
18:73–75. [PubMed: 6772551]
6. Cheng AL, Hsu CH. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with
high-risk or pre-malignant lesions. Anticancer Res. 2001; 21:2895–2900. [PubMed: 11712783]

Anticancer Agents Med Chem. Author manuscript; available in PMC 2014 September 01.
 Beevers et al. Page 8

7. Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, Pirmohamed M, Marnett
LJ, Gescher AJ, Steward WP. Pharmacodynamic and pharmacokinetic study of oral Curcuma
extract in patients with colorectal cancer. Clin Cancer Res. 2001; 7:1894–1900. [PubMed:
NIH-PA Author Manuscript

11448902]
8. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems
and promises. Mol Pharm. 2007; 4:807–818. [PubMed: 17999464]
9. Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv
Exp Med Biol. 2007; 595:453–470. [PubMed: 17569224]
10. Beevers CS, Huang S. Pharmacological and clinical properties of curcumin. Botanics: Targets and
Therapy. 2011; 1:5–18.
11. Basnet P, Skalko-Basnet N. Curcumin: an anti-inflammatory molecule from a curry spice on the
path to cancer treatment. Molecules. 2011; 16:4567–4598. [PubMed: 21642934]
12. Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets. 2011; 12:332–347.
[PubMed: 20955148]
13. Gupta SC, Kim JH, Prasad S, Aggarwal BB. Regulation of survival, proliferation, invasion,
angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by
nutraceuticals. Cancer Metastasis Rev. 2010; 29:405–434. [PubMed: 20737283]
14. Deodhar SD, Sethi R, Srimal RC. Preliminary study on antirheumatic activity of curcumin
(diferuloyl methane). Indian J Med Res. 1980; 71:632–634. [PubMed: 7390600]
15. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current
clinical trials. Cell Mol Life Sci. 2008; 65:1631–1652. [PubMed: 18324353]
NIH-PA Author Manuscript

16. Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS,
Badmaev V, Kurzrock R. Phase II trial of curcumin in patients with advanced pancreatic cancer.
Clin Cancer Res. 2008; 14:4491–4499. [PubMed: 18628464]
17. Sharma RA, Euden SA. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and
compliance. Clin Cancer Res. 2004; 10:6847–6854. [PubMed: 15501961]
18. Kuttan R, Sudheeran PC, Josph CD. Turmeric and curcumin as topical agents in cancer therapy.
Tumori. 1987; 73:29–31. [PubMed: 2435036]
19. Hanif R, Qiao L, Shiff SJ, Rigas B. Curcumin, a natural plant phenolic food additive, inhibits cell
proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-
independent pathway. J Lab Clin Med. 1997; 130:576–584. [PubMed: 9422331]
20. Beevers CS, Li F, Liu L, Huang S. Curcumin inhibits the mammalian target of rapamycin-
mediated signaling pathways in cancer cells. Int J Cancer. 2006; 119:757–764. [PubMed:
16550606]
21. Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Mammalian TOR: a
homeostatic ATP sensor. Science. 2001; 294:1102–1105. [PubMed: 11691993]
22. Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, Kasuga M, Nishimoto I,
Avruch J. Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem. 1997; 272:26457–
26463. [PubMed: 9334222]
NIH-PA Author Manuscript

23. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini
DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell
growth machinery. Cell. 2002; 110:163–175. [PubMed: 12150925]
24. Zhou H, Huang S. The complexes of mammalian target of rapamycin. Curr Protein Pept Sci. 2011;
11:409–424. [PubMed: 20491627]
25. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004; 18:1926–1945.
[PubMed: 15314020]
26. Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S. Curcumin disrupts the Mammalian
target of rapamycin-raptor complex. Cancer Res. 2009; 69:1000–1008. [PubMed: 19176385]
27. Johnston SR. Targeting downstream effectors of epidermal growth factor receptor/HER2 in breast
cancer with either farnesyltransferase inhibitors or mTOR antagonists. Int J Gynecol Cancer. 2006;
16(Suppl 2):543–548. [PubMed: 17010069]
28. LeRoith D, Roberts CT Jr. The insulin-like growth factor system cancer. Cancer Lett. 2003;
195:127–137. [PubMed: 12767520]

Anticancer Agents Med Chem. Author manuscript; available in PMC 2014 September 01.
 Beevers et al. Page 9

29. Carver DJ, Aman MJ, Ravichandran KS. SHIP inhibits Akt activation in B cells through regulation
of Akt membrane localization. Blood. 2000; 96:1449–1456. [PubMed: 10942391]
30. Kohn AD, Takeuchi F, Roth RA. Akt, a pleckstrin homology domain containing kinase, is
NIH-PA Author Manuscript

activated primarily by phosphorylation. J Biol Chem. 1996; 271:21920–21926. [PubMed:

8702995]
31. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, Sabatini DM. mSin1 is
necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr
Biol. 2006; 16:1865–1870. [PubMed: 16919458]
32. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by
the rictor-mTOR complex. Science. 2005; 307:1098–1101. [PubMed: 15718470]
33. Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R,
Magnuson MA, Alessi DR. Identification of Protor as a novel Rictor-binding component of mTOR
complex-2. Biochem J. 2007; 405:513–522. [PubMed: 17461779]
34. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-
kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl
Acad Sci U S A. 1999; 96:4438–4442. [PubMed: 10200280]
35. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E,
Bos JL, Thomas G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is
inhibited by TSC1 and 2. Mol Cell. 2003; 11:1457–1466. [PubMed: 12820960]
36. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase.
Curr Biol. 2005; 15:702–713. [PubMed: 15854902]
NIH-PA Author Manuscript

37. Long X, Ortiz-Vega S, Lin Y, Avruch J. Rheb binding to mammalian target of rapamycin (mTOR)
is regulated by amino acid sufficiency. J Biol Chem. 2005; 280:23433–23436. [PubMed:
15878852]
38. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P,
Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the
nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003; 11:895–904. [PubMed:
12718876]
39. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM.
PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007; 25:903–
915. [PubMed: 17386266]
40. Dufner A, Thomas G. Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res.
1999; 253:100–109. [PubMed: 10579915]
41. Pullen N, Thomas G. The modular phosphorylation and activation of p70s6k. FEBS Lett. 1997;
410:78–82. [PubMed: 9247127]
42. Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ, Avruch J. Regulation of the p70 S6
kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J
Biol Chem. 1998; 273:16621–16629. [PubMed: 9632736]
43. Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr, Sonenberg N. Insulin-
dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function.
NIH-PA Author Manuscript

Nature. 1994; 371:762–767. [PubMed: 7935836]

44. Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD,
Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is
modulated by S6 kinases. Embo J. 2004; 23:1761–1769. [PubMed: 15071500]
45. Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende
M, Sonenberg N. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its
phosphorylation and activity. Embo J. 2006; 25:2781–2791. [PubMed: 16763566]
46. Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation
preinitiation complex through dynamic protein interchange and ordered phosphorylation events.
Cell. 2005; 123:569–580. [PubMed: 16286006]
47. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes
Dev. 2001; 15:807–826. [PubMed: 11297505]

Anticancer Agents Med Chem. Author manuscript; available in PMC 2014 September 01.
 Beevers et al. Page 10

48. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD,
Wyslouch-Cieszynska A, Aebersold R, Sonenberg N. Hierarchical phosphorylation of the
translation inhibitor 4E-BP1. Genes Dev. 2001; 15:2852–2864. [PubMed: 11691836]
NIH-PA Author Manuscript

49. Tokunaga C, Yoshino K, Yonezawa K. mTOR integrates amino acid- and energy-sensing
pathways. Biochem Biophys Res Commun. 2004; 313:443–446. [PubMed: 14684182]
50. Sarbassov DD, Sabatini DM. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and
complex. J Biol Chem. 2005; 280:39505–39509. [PubMed: 16183647]
51. Magagnin MG, van den Beucken T, Sergeant K, Lambin P, Koritzinsky M, Devreese B, Wouters
BG. The mTOR target 4E-BP1 contributes to differential protein expression during normoxia and
hypoxia through changes in mRNA translation efficiency. Proteomics. 2008; 8:1019–1028.
[PubMed: 18219697]
52. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR
signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 2008;
22:239–251. [PubMed: 18198340]
53. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;
124:471–484. [PubMed: 16469695]
54. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR
and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002; 16:1472–1487. [PubMed:
12080086]
55. Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S. Rapamycin inhibits cell motility by
suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene. 2006; 25:7029–7040.
NIH-PA Author Manuscript

[PubMed: 16715128]
56. Edinger AL, Thompson CB. Akt maintains cell size and survival by increasing mTOR-dependent
nutrient uptake. Mol Biol Cell. 2002; 13:2276–2288. [PubMed: 12134068]
57. Huang S, Shu L, Easton J, Harwood FC, Germain GS, Ichijo H, Houghton PJ. Inhibition of
mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by
suppressing protein phosphatase 5 activity. J Biol Chem. 2004; 279:36490–36496. [PubMed:
15218033]
58. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease.
Nat Genet. 2005; 37:19–24. [PubMed: 15624019]
59. Tee AR, Blenis J. mTOR, translational control and human disease. Semin Cell Dev Biol. 2005;
16:29–37. [PubMed: 15659337]
60. Kwiatkowski DJ. Tuberous sclerosis: from tubers to mTOR. Ann Hum Genet. 2003; 67:87–96.
[PubMed: 12556239]
61. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and
tumorigenesis. J Cell Biol. 2004; 167:399–403. [PubMed: 15533996]
62. Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity,
diabetes and cancer. Trends Mol Med. 2007; 13:252–259. [PubMed: 17452018]
63. Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P, Arrieumerlou C, Hall MN. PRAS40
NIH-PA Author Manuscript

and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One. 2007;
2:e1217. [PubMed: 18030348]
64. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007; 12:9–22.
[PubMed: 17613433]
65. Rubio-Viqueira B, Hidalgo M. Targeting mTOR for cancer treatment. Adv Exp Med Biol. 2006;
587:309–327. [PubMed: 17163174]
66. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald
KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals
that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell.
2006; 11:859–871. [PubMed: 17141160]
67. Polak P, Hall MN. mTORC2 Caught in a SINful Akt. Dev Cell. 2006; 11:433–434. [PubMed:
17011481]
68. Peng T, Golub TR, Sabatini DM. The immunosuppressant rapamycin mimics a starvation-like
signal distinct from amino acid and glucose deprivation. Mol Cell Biol. 2002; 22:5575–5584.
[PubMed: 12101249]

Anticancer Agents Med Chem. Author manuscript; available in PMC 2014 September 01.
 Beevers et al. Page 11

69. Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all
three classes of nuclear RNA polymerases. Oncogene. 2006; 25:6384–6391. [PubMed: 17041624]
70. Roos S, Jansson N, Palmberg I, Saljo K, Powell TL, Jansson T. Mammalian target of rapamycin in
NIH-PA Author Manuscript

the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J
Physiol. 2007; 582:449–459. [PubMed: 17463046]
71. Ramirez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ. eIF4GI links nutrient
sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol. 2008; 181:293–
307. [PubMed: 18426977]
72. Mammucari C, Schiaffino S, Sandri M. Downstream of Akt: FoxO3 and mTOR in the regulation
of autophagy in skeletal muscle. Autophagy. 2008; 4:524–526. [PubMed: 18367868]
73. Shinojima N, Yokoyama T, Kondo Y, Kondo S. Roles of the Akt/mTOR/p70S6K and ERK1/2
signaling pathways in curcumin-induced autophagy. Autophagy. 2007; 3:635–637. [PubMed:
17786026]
74. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005; 17:158–
166. [PubMed: 15780592]
75. Mayer C, Zhao J, Yuan X, Grummt I. mTOR-dependent activation of the transcription factor TIF-
IA links rRNA synthesis to nutrient availability. Genes Dev. 2004; 18:423–434. [PubMed:
15004009]
76. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex
2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004; 6:1122–1128.
[PubMed: 15467718]
NIH-PA Author Manuscript

77. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P,
Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and
raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004; 14:1296–1302.
[PubMed: 15268862]
78. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif
phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1).
Biochem J. 2008; 416:375–385. [PubMed: 18925875]
79. Plas DR, Thompson CB. Akt activation promotes degradation of tuberin and FOXO3a via the
proteasome. J Biol Chem. 2003; 278:12361–12366. [PubMed: 12517744]
80. Li Y, Tennekoon GI, Birnbaum M, Marchionni MA, Rutkowski JL. Neuregulin signaling through
a PI3K/Akt/Bad pathway in Schwann cell survival. Mol Cell Neurosci. 2001; 17:761–767.
[PubMed: 11312610]
81. Wan X, Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist. 2007; 12:1007–
1018. [PubMed: 17766661]
82. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt
signaling through an IGF-1R-dependent mechanism. Oncogene. 2007; 26:1932–1940. [PubMed:
17001314]
83. Hosoi H, Dilling MB, Shikata T, Liu LN, Shu L, Ashmun RA, Germain GS, Abraham RT,
Houghton PJ. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-
NIH-PA Author Manuscript

independent apoptosis in human rhabdomyosarcoma cells. Cancer Res. 1999; 59:886–894.

[PubMed: 10029080]
84. Li M, Zhang Z, Hill DL, Wang H, Zhang R. Curcumin, a dietary component, has anticancer,
chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene
through the PI3K/mTOR/ETS2 pathway. Cancer Res. 2007; 67:1988–1996. [PubMed: 17332326]
85. Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y. Evidence that curcumin
suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy:
role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol. 2007;
72:29–39. [PubMed: 17395690]
86. Johnson SM, Gulhati P, Arrieta I, Wang X, Uchida T, Gao T, Evers BM. Curcumin inhibits
proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res. 2009;
29:3185–3190. [PubMed: 19661333]

Anticancer Agents Med Chem. Author manuscript; available in PMC 2014 September 01.
 Beevers et al. Page 12

87. Lim HW, Lim HY, Wong KP. Uncoupling of oxidative phosphorylation by curcumin: implication
of its cellular mechanism of action. Biochem Biophys Res Commun. 2009; 389:187–192.
[PubMed: 19715674]
NIH-PA Author Manuscript

88. Rafiee P, Binion DG, Wellner M, Behmaram B, Floer M, Mitton E, Nie L, Zhang Z, Otterson MF.
Modulatory effect of curcumin on survival of irradiated human intestinal microvascular
endothelial cells: role of Akt/mTOR and NF-{kappa}B. Am J Physiol Gastrointest Liver Physiol.
2010; 298:G865–877. [PubMed: 20299603]
89. Clark CA, McEachern MD, Shah SH, Rong Y, Rong X, Smelley CL, Caldito GC, Abreo FW,
Nathan CO. Curcumin inhibits carcinogen and nicotine-induced Mammalian target of rapamycin
pathway activation in head and neck squamous cell carcinoma. Cancer Prev Res (Phila). 2010;
3:1586–1595. [PubMed: 20851953]
90. Sun ZJ, Chen G, Zhang W, Hu X, Liu Y, Zhou Q, Zhu LX, Zhao YF. Curcumin dually inhibits
both mammalian target of rapamycin and nuclear factor-kappaB pathways through a crossed
phosphatidylinositol 3-kinase/Akt/IkappaB kinase complex signaling axis in adenoid cystic
carcinoma. Mol Pharmacol. 2011; 79:106–118. [PubMed: 20959361]
91. Leonhard WN, van der Wal A, Novalic Z, Kunnen SJ, Gansevoort RT, Breuning MH, de Heer E,
Peters DJ. Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling
pathways: in vivo evidence from a Pkd1-deletion model. Am J Physiol Renal Physiol. 2011;
300:F1193–1202. [PubMed: 21345977]
92. Wong TF, Takeda T, Li B, Tsuiji K, Kitamura M, Kondo A, Yaegashi N. Curcumin disrupts
uterine leiomyosarcoma cells through AKT-mTOR pathway inhibition. Gynecol Oncol. 2011;
122:141–148. [PubMed: 21450334]
NIH-PA Author Manuscript

93. Kondo A, Takeda T, Li B, Tsuiji K, Kitamura M, Wong TF, Yaegashi N. Epigallocatechin-3-

gallate potentiates curcumin’s ability to suppress uterine leiomyosarcoma cell growth and induce
apoptosis. Int J Clin Oncol. 2012 [Epub ahead of print].
94. Phillips JM, Clark C, Herman-Ferdinandez L, Moore-Medlin T, Rong X, Gill JR, Clifford JL,
Abreo F, Nathan CO. Curcumin inhibits skin squamous cell carcinoma tumor growth in vivo.
Otolaryngol Head Neck Surg. 2011; 145:58–63. [PubMed: 21493306]
95. Chen T, Shen L, Yu J, Wan H, Guo A, Chen J, Long Y, Zhao J, Pei G. Rapamycin and other
longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells.
Aging Cell. 2011; 10:908–911. [PubMed: 21615676]
96. Yu S, Shen G, Khor TO, Kim JH, Kong AN. Curcumin inhibits Akt/mammalian target of
rapamycin signaling through protein phosphatase-dependent mechanism. Mol Cancer Ther. 2008;
7:2609–2620. [PubMed: 18790744]
97. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein
phosphatase 2A. Trends Biochem Sci. 1999; 24:186–191. [PubMed: 10322434]
98. Westphal RS, Coffee RL Jr, Marotta A, Pelech SL, Wadzinski BE. Identification of kinase-
phosphatase signaling modules composed of p70 S6 kinase-protein phosphatase 2A (PP2A) p21-
activated kinase-PP2A. J Biol Chem. 1999; 274:687–692. [PubMed: 9873003]
99. Nanahoshi M, Nishiuma T, Tsujishita Y, Hara K, Inui S, Sakaguchi N, Yonezawa K. Regulation of
NIH-PA Author Manuscript

protein phosphatase 2A catalytic activity by alpha4 protein and its yeast homolog Tap42. Biochem
Biophys Res Commun. 1998; 251:520–526. [PubMed: 9792806]
100. Dey R, Majumder N, Bhattacharjee S, Majumdar SB, Banerjee R, Ganguly S, Das P, Majumdar
S. Leishmania donovani-induced ceramide as the key mediator of Akt dephosphorylation in
murine macrophages: role of protein kinase Czeta and phosphatase. Infect Immun. 2007;
75:2136–2142. [PubMed: 17220321]

Anticancer Agents Med Chem. Author manuscript; available in PMC 2014 September 01.
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Fig. 1.
The mTOR signaling pathway. mTOR functions as two distinct signaling complexes,
NIH-PA Author Manuscript

mTORC1 and mTORC2. mTOR signaling regulates multiple cellular processes by sensing
nutrients, energy, growth factors and stress. Arrows represent activation, whereas bars
represent inhibition. IRS, insulin receptor substrates; PIP2, phosphatidylinositol (4, 5)-
bisphosphate; PIP3, phosphatidylinositol-3, 4, 5-trisphosphate; PDK1, phosphoinositide-
dependent kinase 1; TSC, tuberous sclerosis complex; Rheb, Ras homolog enriched in brain;
AMPK, AMP-activated kinase; Grb10, growth factor receptor-bound protein 10.
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