Verticillin通过DNA甲基化上调BNIP3能够克服人结肠癌凋亡的耐药性

Cancer Res 2011 Nov;71(21):6807-16. [IF:8.234]  

Verticillin A Overcomes Apoptosis Resistance in Human Colon Carcinoma through DNA Methylation-Dependent Upregulation of BNIP3.

Liu F , Liu Q , Yang D , Bollag WB , Robertson K , Wu P , Liu K .

Authors' Affiliations: College of Life Sciences, and University Hospital, Zhejiang University, Hangzhou, PR China; Departments of Biochemistry and Molecular Biology and Physiology, and Cancer Research Center, Georgia Health Sciences University, Augusta, Georgia.

杭州浙江大学生命科学学院，浙江大学附属医院，美国佐治亚州卫生科学大学癌症研究中心，美国佐治亚州卫生科学大学生物化学与分子生物学及生理学系

Abstract

Drug resistance is a major cause of failure in cancer chemotherapy. Therefore, identification and combined use of adjuvant compounds that can overcome drug resistance may improve the efficacy of cancer therapy. We screened extracts of Verticillium species-infected mushrooms for antitumor compounds and identified the compound Verticillin A as an inducer of hepatoma cell apoptosis in vitro and an inhibitor of tumor xenograft growth in vivo. Verticillin A exhibited a potent apoptosis-sensitizing activity in human colon carcinoma cells exposed to TRAIL or Fas in vitro. Furthermore, Verticillin A effectively sensitized metastatic human colon carcinoma xenograft to TRAIL-mediated growth inhibition in vivo. At the molecular level, we observed that Verticillin A induces cell-cycle arrest in the G(2) phase of the cell cycle in human colon carcinoma cells, markedly upregulating BNIP3 in both hepatoma and colon carcinoma cells. Notably, silencing BNIP3 decreased the sensitivity of tumor cells to Verticillin A-induced apoptosis in the absence or presence of TRAIL. We found that the BNIP3 promoter is methylated in both human hepatoma and colon carcinoma cells and tumor specimens. Verticillin A upregulated the expression of a panel of genes known to be regulated at the level of DNA methylation, in support of the concept that Verticillin A may act by demethylating the BNIP3 promoter to upregulate BNIP3 expression. Taken together, our findings identify Verticillin A as a potent apoptosis sensitizer with great promise for further development as an adjuvant agent to overcome drug resistance in human cancer therapy. Cancer Res; 71(21); 6807-16. ?2011 AACR.