One protein AMPK kinases including TGF-?-activated kinase-1 (TAK1),

One of the central regulators of cellular
metabolism and energy homeostasis is the AMP-activated protein kinase (AMPK),
which is activated in response to increasing cellular AMP/ATP ratio (which
reflects a decrease in energy supply) (1-3).
 In response, AMPK promotes the activity of several enzymes to enhance
catabolic pathways to produce more ATP,
and limits anabolic pathways. Under lowered intracellular ATP levels, ADP
or AMP can directly bind to the regulatory subunit of AMPK, results in a
conformational change that promotes its activation. In addition to nucleotide
binding, AMPK is activated by upstream protein AMPK kinases including
TGF-?-activated kinase-1 (TAK1), calmodulin-dependent protein kinase kinase ? (CamKK?) and liver kinase B1
(LKB1) (1, 2, 4).

AMPK as a metabolic sensor plays critical role in
regulating growth and reprogramming metabolism
and is linked to cellular processes including apoptosis and inflammation (5, 6). Increasing number of studies
have reported considerable advances in understanding the role of AMPK-mediated
pathways in cancers and inflammatory diseases, diabetes and obesity, atherosclerosis
and metabolic diseases. Many of these diseases are essentially
problems resulting from a positive energy balance, and it was predicted that
activators of AMPK such as curcumin might be useful for treating these
disorders.

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One well-described mechanism by which AMPK
regulates cell growth is through the inhibition of mammalian target of the rapamycin complex (mTOR) pathway by direct
phosphorylation of tuberous sclerosis complex (TSC) (7, 8). mTOR involves in the control of mRNA translation through phosphorylation of downstream
effectors responsible for encoding proteins necessary for cell cycle regulation
and progression (9). Beyond effects on mTOR, other reported targets
of AMPK are the tumor suppressor p53 and cyclin-dependent kinase (CDK)
inhibitors p21WAF1 and p27CIP1 related to cell cycle arrest (10-14). Moreover,
AMPK is the upstream kinase for the critical metabolic enzymes involved in
fatty acid and cholesterol synthesis, including Acetyl-CoA carboxylase (ACC)
and HMG-CoA reductase (3). In addition, glucose uptake is regulated via AMPK by effects
on GLUT4 trafficking in specialized tissues such as muscle and fat (15). In
line with this finding, AMPK inhibits glycolysis and also suppresses gene expression
of gluconeogenic enzymes including phosphoenolpyruvate carboxykinase (PEPCK)
and glucose-6 phosphatase (G6Pase) which prevent hepatic glucose production (16, 17). Generally, given the key role of AMPK in
energy homeostasis, it seems to be a therapeutic target for cancer, obesity,
inflammatory disease and type 2 diabetes (18, 19). Taken
together, AMPK has a central role in the regulation of metabolism and
inflammation and also can be targeted for various cancer therapies.

?Curcumin

Curcumin
is a polyphenolic molecule, derived from the rhizomes of Curcuma longa, a plant
in the ginger family. Curcumin is a bioactive compound being renowned for its
potential anti-inflammatory, antioxidant, anti-proliferative, anti-diabetic and
anti-cancer activities (20-23). Curcumin’s
pleiotropic activities come from its ability to regulate several molecules
in intracellular signal transduction pathways including p53, NF-?B and
NF-?B-regulated gene expression, Akt, cyclin D1, cyclooxygenase-2 (COX-2),
NF-E2-related factor 2 (Nrf2), matrix metalloproteinase-9 (MMP-9), ?-catenin,
mTOR, and mitogen activate protein kinase (MAPK). Accumulating evidence indicates
that curcumin also exerts its therapeutic effects via regulating AMPK which
could lead to the regulation of underlying cellular and molecular pathways
implicated in varieties of diseases such as cancers, diabetes, and
atherosclerosis (21, 24).

Considering
the involvement of curcumin in modulating a number of proteins expression and
signaling pathways, a great number of in vitro and in vivo
studies have explored the curcumin mechanisms of action, and its
pharmacological effects (23, 25-27). In
fact, curcumin can modulate various downstream pathways by having a large
number of interactions with different molecular targets (28). In this aspect, increasing evidence has
addressed the implication of curcumin in modulating AMP kinase pathway, which
could be considered as one of the key targets of curcumin since AMP kinase
stands at the center of various downstream processes (29, 30).
Considering the role of AMP kinase in cell growth, autophagy, anabolic as well
as catabolic metabolic processes, the interaction between curcumin and AMP
kinase pathway has recently gained a great interest in cancer therapy based on
its anti-tumorigenic activities against a number of aggressive malignancies (29-32).

The
biological and pharmacological properties of curcumin have been widely
investigated in epidemiological, clinical, cell culture and animal studies. The
results of these studies elucidate that curcumin and its derivatives have a
potential therapeutic effect on cardiovascular, diabetic, and neurodegenerative
disorders, as well as cancers. Accumulating evidence suggests that curcumin
possesses amazing effects on different signaling targets. In 2008, for the
first time, Pen et al demonstrated that AMPK is a new molecular target of
curcumin (31).

For
detailed overview about the chemical and physical properties and pharmacokinetics
profiles of curcumin, the readers are referred to the reviews of B. B. Aggarwal
and colleagues (24, 33).

Anti-cancer effects

Now, it is
increasingly recognized that curcumin and its derivatives disrupt multiple
components of the signaling pathways and molecular mechanisms that are involved
in the initiation and progression of various cancers. Increasing evidence
indicates that curcumin positively regulates AMPK activity by promoting the phosphorylation
of AMPK (17, 31, 34-38). Several
investigations reported that activation of AMPK triggered by curcumin induces cell cycle arrest and apoptosis in
cancer cells. For instance, Lee et al
indicated that curcumin exhibits apoptotic effects and inhibits cell
proliferation through the AMPK activation. Furthermore, in curcumin-treated
colon cancer cells, the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway is
important in cell proliferation and apoptosis (36).
Further study suggests that curcumin exerts anti-differentiation effect and inhibits
cancer cell growth via regulating AMPK signaling pathway and its possible
substrates, including P38, cyclooxygenase-2 (COX-2) and Peroxisome
proliferator-activated receptor-gamma (PPAR-?) (32). Similarly,
the curcumin-dependent activation of AMPK strongly induces apoptosis and death
of ovarian cancer cells via a p38-dependent mechanism (31).

Curcumin
is considered a potential candidate for the treatment and prevention of cancer
metastasis. The expression/activation of urokinase plasminogen activator (uPA)
and matrix metalloproteinase 9 (MMP-9) play an important role in tumor invasion
and metastasis, and they are overexpressed in many human cancers such as colon
cancer. It has been reported that the pharmacological inhibition of AMPK by
compound C impaired curcumin-mediated inhibition of NF-?B, uPA, and MMP9 in
colon cancer cells. This effect may afford a decrease in expression of uPA and
MMP9 through decreasing NF-?B binding to the promoter of the uPA and MMP-9
genes. Thus, these results indicate that the anti-metastatic effect of curcumin
may be due to AMPK activation and subsequent inhibition of NF-?B, uPA and MMP9
(21).

In another study, curcumin stimulates autophagy in
lung adenocarcinoma cells through activating the AMPK signaling pathway.
Moreover, inhibition of AMPK signaling by compound C or AMPKa1 knockdown
abrogated the induction of autophagy triggered by curcumin (22). In addition,
previous studies have made evident that curcumin can inhibit proliferation of
cancer cells and induced cell injury in these cells, but the specific signaling
pathways involved are not completely clear (22, 30).

In
addition, AMPK is involved in down-regulation
of protein synthesis by the inhibition of mTOR signaling, and by the inhibition
of the elongation step of protein synthesis, sites that are correlated with the
induction of cell growth and proliferation (39). Several studies demonstrated that curcumin
inhibits mTOR signaling in AMPK-dependent and -independent pathways. Shieh et
al. reported that Demethoxycurcumin (DMC),
a natural demethoxy derivative of
curcumin, inhibits the kinase activity of mTORC1 by activating AMPK in breast
cancer cells. The roles of mTOR in mammalian cells are associated with the
control of mRNA translation by phosphorylation of downstream effectors such as
the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1). A hyper-phosphorylated form of 4E-BP1 initiates
translation of a variety of mRNAs, including those encoding proteins involved
in cell cycle regulation and those required for cell cycle progression. DMC
inhibits 4E-BP1 signaling and mRNA translation through the AMPK-mTORC1 pathway and reduces the activity
and/or expression fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) (40).

Many
cancer cells shift their metabolism toward a glycolytic phenotype even under
normal levels of oxygen concentration to provide the biosynthetic requirements
to maintain uncontrolled proliferation and growth and helping in the adaptation
to challenging microenvironments. Thus, glycolytic enzymes are often
upregulated in cancer cells. Zhang et al. indicated that curcumin causes a
significant dose-dependent down-regulation of glycolytic enzymes expressions in
esophageal cancer cells via AMPK activation (41).

Anti-diabetic effects

According
to the World Health Organization (WHO), diabetes is a chronic metabolic disease
which affects over 422 million people worldwide, leading to serious damages to
blood vessels, eyes, kidneys, and nerves (42). The effect of curcumin on AMPK activation on
diabetes has been investigated in several studies. In line with this, Fujiwara
et al. showed that curcumin reduces glucose production in isolated mice
hepatocytes. Accordingly, the results of this study indicate that curcumin
activates AMPK and this activation suppresses gene expression of gluconeogenic
enzymes including glucose-6 phosphatase (G6Pase) and phosphoenolpyruvate
carboxykinase (PEPCK), which suppresses hepatic glucose production in an
insulin-independent manner (43). Moreover,
the anti-diabetic potential of curcumin and its metabolite tetrahydrocurcuminoids (THC) were examined by
Kim et al. They reported that the curcumin and its metabolite (THC), activate
AMPK and suppress gluconeogenic gene expression in rat hepatoma and human
hepatoma cells (17). Similarly, Kang and Kim observed phosphorylation
of AMPK triggered by curcumin plays a beneficial role in glucose metabolism in
differentiated skeletal muscle cells. Moreover, the authors found that curcumin
also improves insulin sensitivity which is mediated by glucose transporter 4
(GLUT4) translocation via AMPK-ACC and Akt pathways in muscle cells (44). These
results may explain the glucose-lowering roles of curcumin and its derivatives.

In
support of the anti-diabetic functions of curcumin-induced
AMPK activation, it has been shown that curcumin inhibits renal triglyceride
accumulation through the AMPK-SREBP pathway in streptozotocin-induced type 1
diabetic rats. In addition, curcumin reduces serum levels of triglycerides (45). Similarly,
in the hepatic stellate cell (HSC), curcumin
abrogates the effects of leptin on HSC activation and lipid depletion
correlated with hepatic fibrosis, by activating AMPK. The AMPK activation induces
the expression of genes associated with lipid accumulation and elevates the
level of intracellular lipids (46).

Anti-inflammatory effects

Published
studies indicate that AMPK participates in modulating acute or chronic
in?ammatory processes in different cells or animal models (47-49). Anti-inflammatory
effects of curcumin result from its ability to inhibit the proinflammatory
transcription factors including NF-?B, and to activate PPAR? cell-signaling
pathways (50, 51). Thus,
it is possible that AMPK activation by curcumin inhibits the ability of NF-?B
to induce nuclear transcription via its downstream mediators, which downregulates
in?ammatory response.

Kim et
al. provided evidence that curcumin increases phosphorylation of AMPK and its
downstream effector Acetyl-CoA carboxylase (ACC) in lipopolysaccharide
(LPS)-treated macrophages, which was thought to be partially related to its
anti-inflammatory activity. It is possible that AMPK activation occurs through
Ca2/calmodulin-dependent protein kinase
kinase (CaMKK) modulation and decreased LPS-induced activation of macrophages.
Curcumin also decreases LPS-induced phosphorylation and degradation of I?B?, a
negative regulator of NF-?B, and diminishes NF-?B-dependent pro-inflammatory
cytokine production such as interleukins IL-6, tumor necrosis factor (TNF-?)
and macrophage inflammatory protein (MIP)-2 (52). In
addition, Tong et al. observed curcumin suppresses the activation of
inflammatory transcription factor NF-?B in a dose-dependent manner (34).

Anti-atherogenic effects

Atherosclerosis
is a vascular disease characterized by lipid accumulation and chronic
inflammation in arterial walls (53). There
are several studies supporting the inflammatory- and lipid-lowering effects of
curcumin and the therapeutic potency of this agent in atherosclerosis pathology
(45, 54-56). In
addition, AMPK has emerged as a therapeutic target for the treatment of
atherosclerosis (57). In
line with these findings, it has been shown that curcumin inhibits adipocyte differentiation
by activating AMPK via its downstream PPAR-? (32). A
study performed by Cao et al indicated
that curcumin attenuates the expression of MMP-9 and MMP-13 in monocyte and
macrophage during differentiation by inhibiting AMPK-mitogen-activated protein kinase (MAPK) pathway (58). Increasing expression and activity of MMP-9 and MMP-13 are related with
atherosclerotic lesions followed by plaque rupture and myocardial infarction (59-61).

A key
part of atherosclerosis is the failure of macrophages to successfully perform
their scavenger role and the formation of foam cells. In 2015, Lin et al.
examined the effect of curcumin on cellular cholesterol levels and reported
curcumin activates AMPK and its downstream target SIRT1. Curcumin markedly up-regulates ATP-binding cassette transporter 1
(ABCA1) expression mediated by activating the AMPK-SIRT1-LXR?
pathway in macrophage-derived foam cells. Likewise, curcumin induces
cholesterol efflux and reduces cellular cholesterol levels (62).

Conclusion

The use of curcumin holds promise in the
treatment of cancer, and AMPK, one of the major pathways in the regulation
of cellular processes, is activated by curcumin and its derivatives. Activation
of AMPK by curcumin leads to increased cancer cell apoptosis and inhibits cell
proliferation. Curcumin also exerts anti-differentiation effect and inhibits
cancer cell growth via regulating AMPK signaling pathway. Thus, targeting AMPK can be used to
protect from cancer, diabetes, and other inflammatory diseases. This review
summarizes current knowledge about the role of curcumin in activating AMPK signaling
pathway in the pathogenesis of proinflammatory diseases
including cancer, atherosclerosis and diabetes for a better understanding and
hence a better management of these diseases.

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