Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism.
Akt/mammalian target of rapamycin (mTOR) signaling plays an important role in tumorigenesis and is dysregulated in many tumors, especially metastatic prostate cancers. Curcumin has been shown to effectively prevent or inhibit prostate cancer in vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains unclear. Here, we show that curcumin concentration- and time-dependently inhibited the phosphorylation of Akt, mTOR, and their downstream substrates in human prostate cancer PC-3 cells, and this inhibitory effect acts downstream of phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1. Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin-mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin-mediated inhibition of Akt/mTOR signaling. Curcumin also activated 5'-AMP-activated protein kinase and mitogen-activated protein kinases; however, inhibition of these kinases failed to rescue the inhibition by curcumin. Finally, it was shown that the inhibition of Akt/mTOR signaling by curcumin is resulted from calyculin A-sensitive protein phosphatase-dependent dephosphorylation. Our study reveals the profound effects of curcumin on the Akt/mTOR signaling network in PC-3 cells and provides new mechanisms for the anticancer effects of curcumin.
Yu
Siwang
S
Department of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Shen
Guoxiang
G
Khor
Tin Oo
TO
Kim
Jung-Hwan
JH
Kong
Ah-Ng Tony
AN
D055372:AMP-Activated Protein Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008387:Marine Toxins; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D055372:AMP-Activated Protein Kinases; D002867:Chromones; D003474:Curcumin; D004273:DNA, Neoplasm; D008387:Marine Toxins; D009025:Morpholines; D009097:Multienzyme Complexes; D010080:Oxazoles; D019869:Phosphatidylinositol 3-Kinases; D010749:Phosphoprotein Phosphatases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C059041:calyculin A; C546842:MTOR protein, human
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