期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 235, 期 2, 页码 253-260出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2008.12.009
关键词
Prodigiosin; Survivin; Paclitaxel; Apoptosis; Breast cancer
资金
- National Science Council of Taiwan [NSC 96-2320-B-005-005-MY2]
- Taichung Veterans General Hospital and National Chung Hsing University, Taichung, Taiwan [TCVGH-NCHU-977612]
- Taichung Veterans General Hospital and Central Taiwan University of Science and Technology, Taichung Taiwan [TCVGH-CTUST-977713]
Prodigiosin is a bacterial metabolite with potent anticancer activity, which is attributed to its proapoptotic effect selectively active in malignant cells. Still, the molecular mechanisms whereby prodigiosin induces apoptosis remain largely unknown. In particular, the role of suivivin, a vital inhibitor of apoptosis, in prodigiosin-induced apoptosis has never been addressed before and hence was the primary goal of this study. Our results showed that prodigiosin close-dependently induced down-regulation of survivin in multiple breast carcinoma cell lines, including MCF-7, T-47D and MDA-MB-231. This down-regulation is mainly regulated at the level of transcription, as prodigiosin reduced the levels of both survivin mRNA and survivin promoter activity but failed to rescue survivin expression when proteasome-mediated degradation is abolished. Importantly, overexpression of survivin rendered cells more resistant to prodigiosin, indicating all essential role of survivin down-regulation in prodigiosin-induced apoptosis. In addition, we found that prodigiosin synergistically enhanced cell death induced by paclitaxel, a chemotherapy drug known to up-regulate survivin that ill turn confers its own resistance. This paclitaxel sensitization effect of prodigiosin is ascribed to the lowering of survivin expression, because prodigiosin was shown to counteract survivin induction by paclitaxel and, notably, the sensitization effect was severely abrogated in cells that overexpress survivin. Taken together, our results argue that down-regulation of survivin is all integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitixel, in the treatment of breast cancer. (C) 2008 Elsevier Inc. All rights reserved.
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