One AMPK is activated by upstream protein

One of the central regulators of cellularmetabolism and energy homeostasis is the AMP-activated protein kinase (AMPK),which is activated in response to increasing cellular AMP/ATP ratio (whichreflects a decrease in energy supply) (1-3).

 In response, AMPK promotes the activity of several enzymes to enhancecatabolic pathways to produce more ATP,and limits anabolic pathways. Under lowered intracellular ATP levels, ADPor AMP can directly bind to the regulatory subunit of AMPK, results in aconformational change that promotes its activation. In addition to nucleotidebinding, AMPK is activated by upstream protein AMPK kinases includingTGF-?-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 inregulating growth and reprogramming metabolismand is linked to cellular processes including apoptosis and inflammation (5, 6).

Increasing number of studieshave reported considerable advances in understanding the role of AMPK-mediatedpathways in cancers and inflammatory diseases, diabetes and obesity, atherosclerosisand metabolic diseases. Many of these diseases are essentiallyproblems resulting from a positive energy balance, and it was predicted thatactivators of AMPK such as curcumin might be useful for treating thesedisorders. One well-described mechanism by which AMPKregulates cell growth is through the inhibition of mammalian target of the rapamycin complex (mTOR) pathway by directphosphorylation of tuberous sclerosis complex (TSC) (7, 8). mTOR involves in the control of mRNA translation through phosphorylation of downstreameffectors responsible for encoding proteins necessary for cell cycle regulationand progression (9).

Beyond effects on mTOR, other reported targetsof 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 infatty acid and cholesterol synthesis, including Acetyl-CoA carboxylase (ACC)and HMG-CoA reductase (3). In addition, glucose uptake is regulated via AMPK by effectson GLUT4 trafficking in specialized tissues such as muscle and fat (15). Inline with this finding, AMPK inhibits glycolysis and also suppresses gene expressionof 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 inenergy homeostasis, it seems to be a therapeutic target for cancer, obesity,inflammatory disease and type 2 diabetes (18, 19). Takentogether, AMPK has a central role in the regulation of metabolism andinflammation and also can be targeted for various cancer therapies. ?CurcuminCurcuminis a polyphenolic molecule, derived from the rhizomes of Curcuma longa, a plantin the ginger family. Curcumin is a bioactive compound being renowned for itspotential anti-inflammatory, antioxidant, anti-proliferative, anti-diabetic andanti-cancer activities (20-23). Curcumin’spleiotropic activities come from its ability to regulate several moleculesin intracellular signal transduction pathways including p53, NF-?B andNF-?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 indicatesthat curcumin also exerts its therapeutic effects via regulating AMPK whichcould lead to the regulation of underlying cellular and molecular pathwaysimplicated in varieties of diseases such as cancers, diabetes, andatherosclerosis (21, 24).

Consideringthe involvement of curcumin in modulating a number of proteins expression andsignaling pathways, a great number of in vitro and in vivostudies have explored the curcumin mechanisms of action, and itspharmacological effects (23, 25-27). Infact, curcumin can modulate various downstream pathways by having a largenumber of interactions with different molecular targets (28). In this aspect, increasing evidence hasaddressed the implication of curcumin in modulating AMP kinase pathway, whichcould be considered as one of the key targets of curcumin since AMP kinasestands at the center of various downstream processes (29, 30).Considering the role of AMP kinase in cell growth, autophagy, anabolic as wellas catabolic metabolic processes, the interaction between curcumin and AMPkinase pathway has recently gained a great interest in cancer therapy based onits anti-tumorigenic activities against a number of aggressive malignancies (29-32).

Thebiological and pharmacological properties of curcumin have been widelyinvestigated in epidemiological, clinical, cell culture and animal studies. Theresults of these studies elucidate that curcumin and its derivatives have apotential therapeutic effect on cardiovascular, diabetic, and neurodegenerativedisorders, as well as cancers. Accumulating evidence suggests that curcuminpossesses amazing effects on different signaling targets. In 2008, for thefirst time, Pen et al demonstrated that AMPK is a new molecular target ofcurcumin (31).Fordetailed overview about the chemical and physical properties and pharmacokineticsprofiles of curcumin, the readers are referred to the reviews of B.

B. Aggarwaland colleagues (24, 33).Anti-cancer effectsNow, it isincreasingly recognized that curcumin and its derivatives disrupt multiplecomponents of the signaling pathways and molecular mechanisms that are involvedin the initiation and progression of various cancers. Increasing evidenceindicates that curcumin positively regulates AMPK activity by promoting the phosphorylationof AMPK (17, 31, 34-38). Severalinvestigations reported that activation of AMPK triggered by curcumin induces cell cycle arrest and apoptosis incancer cells. For instance, Lee et alindicated that curcumin exhibits apoptotic effects and inhibits cellproliferation through the AMPK activation. Furthermore, in curcumin-treatedcolon cancer cells, the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway isimportant in cell proliferation and apoptosis (36).Further study suggests that curcumin exerts anti-differentiation effect and inhibitscancer cell growth via regulating AMPK signaling pathway and its possiblesubstrates, including P38, cyclooxygenase-2 (COX-2) and Peroxisomeproliferator-activated receptor-gamma (PPAR-?) (32).

Similarly,the curcumin-dependent activation of AMPK strongly induces apoptosis and deathof ovarian cancer cells via a p38-dependent mechanism (31). Curcuminis considered a potential candidate for the treatment and prevention of cancermetastasis. The expression/activation of urokinase plasminogen activator (uPA)and matrix metalloproteinase 9 (MMP-9) play an important role in tumor invasionand metastasis, and they are overexpressed in many human cancers such as coloncancer. It has been reported that the pharmacological inhibition of AMPK bycompound C impaired curcumin-mediated inhibition of NF-?B, uPA, and MMP9 incolon cancer cells. This effect may afford a decrease in expression of uPA andMMP9 through decreasing NF-?B binding to the promoter of the uPA and MMP-9genes. Thus, these results indicate that the anti-metastatic effect of curcuminmay be due to AMPK activation and subsequent inhibition of NF-?B, uPA and MMP9(21). In another study, curcumin stimulates autophagy inlung adenocarcinoma cells through activating the AMPK signaling pathway.Moreover, inhibition of AMPK signaling by compound C or AMPKa1 knockdownabrogated the induction of autophagy triggered by curcumin (22).

In addition,previous studies have made evident that curcumin can inhibit proliferation ofcancer cells and induced cell injury in these cells, but the specific signalingpathways involved are not completely clear (22, 30).Inaddition, AMPK is involved in down-regulationof protein synthesis by the inhibition of mTOR signaling, and by the inhibitionof the elongation step of protein synthesis, sites that are correlated with theinduction of cell growth and proliferation (39). Several studies demonstrated that curcumininhibits mTOR signaling in AMPK-dependent and -independent pathways. Shieh etal. reported that Demethoxycurcumin (DMC),a natural demethoxy derivative ofcurcumin, inhibits the kinase activity of mTORC1 by activating AMPK in breastcancer cells.

The roles of mTOR in mammalian cells are associated with thecontrol of mRNA translation by phosphorylation of downstream effectors such asthe eukaryotic initiation factor 4E-binding protein-1 (4E-BP1). A hyper-phosphorylated form of 4E-BP1 initiatestranslation of a variety of mRNAs, including those encoding proteins involvedin cell cycle regulation and those required for cell cycle progression. DMCinhibits 4E-BP1 signaling and mRNA translation through the AMPK-mTORC1 pathway and reduces the activityand/or expression fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) (40).Manycancer cells shift their metabolism toward a glycolytic phenotype even undernormal levels of oxygen concentration to provide the biosynthetic requirementsto maintain uncontrolled proliferation and growth and helping in the adaptationto challenging microenvironments. Thus, glycolytic enzymes are oftenupregulated in cancer cells.

Zhang et al. indicated that curcumin causes asignificant dose-dependent down-regulation of glycolytic enzymes expressions inesophageal cancer cells via AMPK activation (41). Anti-diabetic effectsAccordingto the World Health Organization (WHO), diabetes is a chronic metabolic diseasewhich affects over 422 million people worldwide, leading to serious damages toblood vessels, eyes, kidneys, and nerves (42). The effect of curcumin on AMPK activation ondiabetes has been investigated in several studies. In line with this, Fujiwaraet al.

showed that curcumin reduces glucose production in isolated micehepatocytes. Accordingly, the results of this study indicate that curcuminactivates AMPK and this activation suppresses gene expression of gluconeogenicenzymes including glucose-6 phosphatase (G6Pase) and phosphoenolpyruvatecarboxykinase (PEPCK), which suppresses hepatic glucose production in aninsulin-independent manner (43). Moreover,the anti-diabetic potential of curcumin and its metabolite tetrahydrocurcuminoids (THC) were examined byKim et al. They reported that the curcumin and its metabolite (THC), activateAMPK and suppress gluconeogenic gene expression in rat hepatoma and humanhepatoma cells (17). Similarly, Kang and Kim observed phosphorylationof AMPK triggered by curcumin plays a beneficial role in glucose metabolism indifferentiated skeletal muscle cells.

Moreover, the authors found that curcuminalso improves insulin sensitivity which is mediated by glucose transporter 4(GLUT4) translocation via AMPK-ACC and Akt pathways in muscle cells (44). Theseresults may explain the glucose-lowering roles of curcumin and its derivatives.Insupport of the anti-diabetic functions of curcumin-inducedAMPK activation, it has been shown that curcumin inhibits renal triglycerideaccumulation through the AMPK-SREBP pathway in streptozotocin-induced type 1diabetic rats. In addition, curcumin reduces serum levels of triglycerides (45). Similarly,in the hepatic stellate cell (HSC), curcuminabrogates the effects of leptin on HSC activation and lipid depletioncorrelated with hepatic fibrosis, by activating AMPK. The AMPK activation inducesthe expression of genes associated with lipid accumulation and elevates thelevel of intracellular lipids (46).

Anti-inflammatory effectsPublishedstudies indicate that AMPK participates in modulating acute or chronicin?ammatory processes in different cells or animal models (47-49). Anti-inflammatoryeffects of curcumin result from its ability to inhibit the proinflammatorytranscription factors including NF-?B, and to activate PPAR? cell-signalingpathways (50, 51). Thus,it is possible that AMPK activation by curcumin inhibits the ability of NF-?Bto induce nuclear transcription via its downstream mediators, which downregulatesin?ammatory response. Kim etal. provided evidence that curcumin increases phosphorylation of AMPK and itsdownstream effector Acetyl-CoA carboxylase (ACC) in lipopolysaccharide(LPS)-treated macrophages, which was thought to be partially related to itsanti-inflammatory activity. It is possible that AMPK activation occurs throughCa2/calmodulin-dependent protein kinasekinase (CaMKK) modulation and decreased LPS-induced activation of macrophages.Curcumin also decreases LPS-induced phosphorylation and degradation of I?B?, anegative regulator of NF-?B, and diminishes NF-?B-dependent pro-inflammatorycytokine production such as interleukins IL-6, tumor necrosis factor (TNF-?)and macrophage inflammatory protein (MIP)-2 (52). Inaddition, Tong et al.

observed curcumin suppresses the activation ofinflammatory transcription factor NF-?B in a dose-dependent manner (34). Anti-atherogenic effects Atherosclerosisis a vascular disease characterized by lipid accumulation and chronicinflammation in arterial walls (53). Thereare several studies supporting the inflammatory- and lipid-lowering effects ofcurcumin and the therapeutic potency of this agent in atherosclerosis pathology(45, 54-56). Inaddition, AMPK has emerged as a therapeutic target for the treatment ofatherosclerosis (57). Inline with these findings, it has been shown that curcumin inhibits adipocyte differentiationby activating AMPK via its downstream PPAR-? (32). Astudy performed by Cao et al indicatedthat curcumin attenuates the expression of MMP-9 and MMP-13 in monocyte andmacrophage during differentiation by inhibiting AMPK-mitogen-activated protein kinase (MAPK) pathway (58). Increasing expression and activity of MMP-9 and MMP-13 are related withatherosclerotic lesions followed by plaque rupture and myocardial infarction (59-61).

A keypart of atherosclerosis is the failure of macrophages to successfully performtheir scavenger role and the formation of foam cells. In 2015, Lin et al.examined the effect of curcumin on cellular cholesterol levels and reportedcurcumin 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 inducescholesterol efflux and reduces cellular cholesterol levels (62). ConclusionThe use of curcumin holds promise in thetreatment of cancer, and AMPK, one of the major pathways in the regulationof cellular processes, is activated by curcumin and its derivatives.

Activationof AMPK by curcumin leads to increased cancer cell apoptosis and inhibits cellproliferation. Curcumin also exerts anti-differentiation effect and inhibitscancer cell growth via regulating AMPK signaling pathway. Thus, targeting AMPK can be used toprotect from cancer, diabetes, and other inflammatory diseases. This reviewsummarizes current knowledge about the role of curcumin in activating AMPK signalingpathway in the pathogenesis of proinflammatory diseasesincluding cancer, atherosclerosis and diabetes for a better understanding andhence a better management of these diseases.


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