科研之友
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摘要
Selenium has received much attention as an anticancer agent, although the mechanisms of action underlying its pro-apoptotic properties remain unclear. Tumors that respond well to antioxidant treatments, such as hepatocellular carcinoma (HCC), may benefit from treatment with selenium as this compound also has antioxidant properties. Furthermore, a major oncogenic driver in HCC is the nuclear transcription co-activator, beta-catenin. In the present study, we examined the mechanism by which selenium reduces survival of HCC cells, and whether this was associated with modulation of the beta-catenin pathway. Hep3B cell lines and cancer cell xenografted animals were treated with selenium, and apoptotic events or signals such as AMPK, beta-catenin and GSK3 beta were determined. Further interactions among beta-catenin, glycogen synthase kinase 3 beta (GSK3 beta), and AMPK were explored by applying AMPK small interfering RNA (siRNA) or GSK3 beta siRNA with western blotting or immunofluorescence microscopic observation. Selenium activated AMPK, which in turn suppressed beta-catenin. Selenium induced the translocation of AMPK into the nucleus and prevented the accumulation of beta-catenin therein. Upon inactivation of AMPK by AMPK siRNA, selenium no longer modulated beta-catenin, implying that AMPK is an upstream signal for beta-catenin. We found that the binding between AMPK and beta-catenin occurs in the cytosolic fraction, and therefore concluded that the cancer cell antiproliferative effects of selenium are mediated by a GSK3 beta-independent AMPK/beta-catenin pathway, although AMPK-mediated GSK3 beta regulation was also observed. We primarily discovered that AMPK is a crucial regulator initiating selenium-induced inhibition of beta-catenin expression. Taken together, these novel findings help to illuminate the molecular mechanisms underlying the anticancer effect of selenium and highlight the regulation of beta-catenin by selenium.
- 出版日期2016-3
