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ABSTRACT: It has been well known that resveratrol inhibits the proliferation of various cancer cells. AMP-activated protein kinase (AMPK),
a sensor of cellular energy status, has emerged as a potent target for cancer prevention and/or treatment. It has been found
that the activation of AMPK by resveratrol was crucial for the inhibition of HT-29 colon cancer cells. Resveratrol strongly
inhibited phosphorylation of Akt. The possibility whether AMPK activation was essential to the inhibition of p-Akt was investigated
in resveratrol-treated cancer cells. The inhibitory effect of resveratrol on Akt was not observed when AMPK activities were
blocked by the treatment with AMPK siRNA at a relatively lower level of resveratrol. However, the higher concentrations of
resveratrol inhibited Akt without the activation of AMPK. Therefore, it was concluded that resveratrol could modulate Akt
AMPK-dependently or AMPK-independently. The inhibition of Akt along with the activation of AMPK may contribute to the unraveling
anti-cancer mechanism of resveratrol.
KeywordsAkt–AMP-activated kinase–LY294002–resveratrol–HT-29 colon cancer cell
Food science and biotechnology 04/2012; 19(6):1537-1541. · 0.49 Impact Factor
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ABSTRACT: Activation of the mammalian target of rapamycin (mTOR) pathway promotes tumorigenesis, and inhibiting the mammalian target of rapamycin complex 1 (mTORC1) has emerged as an attractive target for suppressing tumor growth. We found that selenium treatment of HT-29 colon cancer cells suppressed mTORC1 through Akt-independent and -dependent pathways. In Akt-independent mTORC1 inhibition in selenium-treated colon cancer cells, adenosine monophosphate-activated protein kinase (AMPK) alpha(1) was crucial for suppression of mTORC1 activity. In contrast, the Akt-dependent mTORC1 inhibition by selenium did not require AMPKalpha(1). The importance of the AMPKalpha(1)-mTORC1 pathway in mediating the antiproliferative action of selenium was examined in xenograft tumors, and the suppression of mTORC1 as well as Akt was concomitant with an increase in AMPKalpha(1) activity. These findings suggest that the antiproliferative effect of selenium is mediated by an Akt-independent AMPKalpha(1)/mTORC1 pathway or by the Akt/tuberous sclerosis complex 2 /mTORC1 pathway.
Carcinogenesis 02/2010; 31(6):1092-9. · 5.70 Impact Factor
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ABSTRACT: AMP-activated protein kinase (AMPK), a highly conserved protein in eukaryotes, functions as a major metabolic switch to maintain energy homeostasis. It also intrinsically regulates the mammalian cell cycle. Moreover, the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK-cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK-COX-2 cascade. Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 micromol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK. Cell cycle analysis showed that curcumin induced G(1)-phase arrest. Further study with AMPK synthetic inhibitor Compound C has shown that increased concentrations of Compound C would abolish AMPK expression, accompanied by a marked increase in COX-2 as well as pAkt expression in curcumin-treated HT-29 cells. By inhibiting AMPK with Compound C, we found that curcumin-treated colon cancer cells were no longer undergoing apoptosis; rather, they were proliferative. These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.
Annals of the New York Academy of Sciences 09/2009; 1171:489-94. · 3.15 Impact Factor
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ABSTRACT: AMPK (AMP-activated protein kinase) is highly conserved in eukaryotes, where it functions primarily as a sensor of cellular energy status. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumor cells. In this study, quercetin activated AMPK in MCF breast cancer cell lines and HT-29 colon cancer cells, and this activation of AMPK seemed to be closely related to a decrease in COX-2 expression. The application of a COX-2 inhibitor or cox-2-/- cells supported the idea that AMPK is an upstream signal of COX-2, and is required for the anti-proliferatory and pro-apoptotic effects of quercetin. The suppressive or growth inhibitory effects of quercetin on COX-2 were abolished by treating cancer cells with an AMPK inhibitor Compound C. These results suggest that AMPK is crucial to the anti-cancer effect of quercetin and that the AMPK-COX-2 signaling pathway is important in quercetin-mediated cancer control.
Experimental and Molecular Medicine 04/2009; 41(3):201-7. · 2.48 Impact Factor
