The involvement of AMPK/GSK3-beta signals in the control of metastasis and proliferation in hepato-carcinoma cells treated with anthocyanins extracted from Korea wild berry Meoru

BMC Complementary and Alternative Medicine

Young-Min Kim²  Ock Jin Park³  Won Sup Lee¹  Yun-Kyoung Lee⁴  Song Yi Park² 

[1] Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Gyeongnam Regional Cancer Center, Gyeongsang National University Hospital, Jinju 660-702, South Korea;Department of Biological Sciences and Biotechnology, Hannam University Daedeok Valley Campus, 461-6 Jeonmin-dong, Daejeon 305-811 Yuseong-gu, South Korea;Department of Food and Nutrition, Hannam University Daedeok Valley Campus, 461-6 Jeonmin-dong, Daejeon 305-811 Yuseong-gu, South Korea;Department of Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203USA

关键词: Anti-metastatic potential;    Meoru origin anthocyanins;    beta-catenin;    Glycogen synthase kinase 3-beta;    AMP-activated protein kinase;   

Others  :  1220214
DOI  :  10.1186/1472-6882-14-109

 received in 2013-05-08, accepted in 2014-02-27,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Park et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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