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Background: Activation of the Wnt pathway is known to promote tumorigenesis and tumor metastasis, and targeting Wnt pathway inhibition has emerged as an attractive approach for controlling tumor invasion and metastasis. The major pathway for inhibiting Wnt is through the degradation of β-catenin by the GSK3-beta/CK1/Axin/APC complex. It was found that Hep3B hepato-carcinoma cells respond to anthocyanins through GSK3-beta-induced suppression of beta-catenin; however, they cannot dephosphorylate GSK3-beta without AMPK activation. Methods: We tested the effects of anthocyanins on proliferation and apoptosis by MTT and Annexin V-PI staining in vitro. Mouse xenograft models of hepato-carcinomas were established by inoculation with Hep3B cells, and mice were injected with 50 mg/kg/ml of anthocyanins. In addition, protein levels of p-GSK3-beta, beta-catenin, p-AMPK, MMP-9, VEGF, and Ang-1 were also analyzed using western blot. Results: Anthocyanins decrease phospho-GSK3-beta and beta-catenin expression in an in vivo tumor xenograft model, increase AMPK activity in this model, and inhibit cell migration and invasion, possibly by inhibiting MMP-2 (in vitro) and the panendothelial marker, CD31 (in vivo). To elucidate the role of the GSK3-beta/beta-catenin pathway in cancer control, we conditionally inactivated this pathway, using activated AMPK for inhibition. Further, we showed that AMPK siRNA treatment abrogated the ability of anthocyanins to control cell proliferation and metastatic potential, and Compound C, an AMPK inhibitor, could not restore GSK3-beta regulation, as exhibited by anthocyanins in Hep3B cells. Conclusion: These observations imply that the AMPK-mediated GSK3-beta/beta-catenin circuit plays crucial roles in inhibiting cancer cell proliferation and metastasis in anthocyanin-treated hepato-carcinoma cells of Meoru origin. [ABSTRACT FROM AUTHOR]

The present study investigated the regulatory mechanisms by which epigallocatechin-3-gallate (EGCG) exerts vascular endothelial growth factor (VEGF)-, p53-and AMP-activated protein kinase (AMPK)-associated pro-apoptotic and migration-suppressing effects on colon cancer cells. EGCG decreased the expression levels of VEGF and matrix metalloproteinase (MMP)-9. EGCG treatment induced apoptosis in the presence of wild-type and mutant p53, indicating that a p53-independent pathway may contribute to EGCG-induced apoptosis in these cells. EGCG showed migration-suppressing effects, suggesting that this activity may also have p53-dependent and -independent components. The interaction between p53 and VEGF in the EGCG-treated cells was investigated using pifithrin-α. Notably, the suppression of p53 activity blocked the ability of EGCG to inhibit VEGF and MMP-9 in the cells expressing wild-type p53, but not mutant p53, indicating that the effects of EGCG on VEGF may be p53-dependent or -independent. Finally, although AMPK and VEGF did not appear to co-localize, the results indicated that AMPK controls VEGF in EGCG-treated cells regardless of the p53 status. [ABSTRACT FROM AUTHOR]

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) α1 was crucial for suppression of mTORC1 activity. In contrast, the Akt-dependent mTORC1 inhibition by selenium did not require AMPKα1. The importance of the AMPKα1–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 AMPKα1 activity. These findings suggest that the antiproliferative effect of selenium is mediated by an Akt-independent AMPKα1/mTORC1 pathway or by the Akt/tuberous sclerosis complex 2 /mTORC1 pathway. [ABSTRACT FROM PUBLISHER]

The antigenotoxic effects of estrogen and genistein (isoflavones) were compared by measuring the degree of protection against plasmid DNA strand breakage induced by peroxyl free radicals using the DNA strand scission assay with pBR322 DNA. Isoflavones decreased DNA strand breakage by AAPH radical treatment at the all of three concentrations tested (0.5, 1.0, 1.5 μg/ml) with the range of 89.5% to 99.6%. Compared to genistein, estrogen was not as effective as genistein showing 46.9% to 29.6% protection, and this protective effect was decreased as estrogen concentrations increased from 0.1 to 0.3 μg/ml. DNA ladder experiments showed that genistein induced apoptosis in cultured cell lines, whereas estrogen did not induce any apoptosis. The effects of cell signal trandsduction protein expression patterns were compared between estrogen and genistein. The increased expression of cyclin B_{1} by estrogen was tampered by genistein at the highest concentration. Antigenotoxic and antiproliferative effects of genistein shown in this study support the hypothesis that it has a chemopreventive effect against particular types of cancers. [ABSTRACT FROM AUTHOR]