Anthocyanins are novel AMPKα1 stimulators that suppress tumor growth by inhibiting mTOR phosphorylation.
AMP-activated protein kinase (AMPK) has emerged as a therapeutic target of cancer. AMPK functions as an upstream regulator of proliferative signals such as mammalian target of rapamycin (mTOR), tuberous sclerosis complex (TSC), p70S6 and elongation factor-2, indicating that AMPK can be applied for the inhibition of cancer cell proliferation via modulating the proliferative signaling network. The Akt/mTOR signaling pathway is activated in colon cancer. The well known mTOR inhibitor rapamycin has a disadvantage of feedback stimulation of Akt. Anthocyanins are naturally-occurring mTOR inhibitor possessing Akt inhibitory activities. We have investigated the mTOR inhibitory effect of anthocyanins through the activation of AMPK. In this study, anthocyanins were applied to colon cancer cells and tumor-bearing xenograft models to investigate their anti-proliferative and pro-apoptotic effects, and elucidate the mechanisms that link AMP-activated protein kinase (AMPK) α1 activation to the survival signal of mTOR. Our results indicated that anthocyanins significantly decreased phospho-mTOR comparable to rapamycin, a synthetic mTOR inhibitor, and this inhibitory effect of anthocyanins on mTOR was completely abrogated by inactivating AMPKα1. Furthermore, suppression of cell growth with anthocyanins was also alleviated in the absence of noticeable AMPKα1 activities. For the first time we have found anthocyanins as novel AMPKα1 activators, and in conditions of AMPKα1 inactivation, anthocyanins lost their ability to inhibit mTOR in HT-29 colon cancer cells. The activation of AMPKα1, and the deactivation of mTOR and Akt were observed in anthocyanins-treated tumor-bearing xenograft models. The results from this study suggest that there is a complex interaction between AMPKα1 and mTOR signaling, and anthocyanins are powerful AMPKα1 activators that inhibit cancer cell growth by inhibiting mTOR phosphorylation.
Department of Food and Nutrition, Hannam University Daedeok Valley Campus, Yuseong-gu, Daejeon 305-811, Korea.
Yun-Kyoung
YK
Lee
Won Sup
WS
Lee
Gon Sup
GS
Kim
Ock Jin
OJ
Park
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000872:Anthocyanins; D000970:Antineoplastic Agents; C546843:mTOR protein, mouse; C548179:Prkaa1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases