Prodigiosin down-regulates survivin to facilitate paclitaxel sensitization in human breast carcinoma cell lines.
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 survivin, 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 dose-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 an 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 in 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 an integral component mediating prodigiosin-induced apoptosis in human breast cancer cells, and further suggest the potential of prodigiosin to sensitize anticancer drugs, including paclitaxel, in the treatment of breast cancer.
Ho
Tsing-Fen
TF
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
Peng
Yu-Ta
YT
Chuang
Show-Mei
SM
Lin
Shin-Chang
SC
Feng
Bo-Lin
BL
Lu
Chien-Hsing
CH
Yu
Wan-Ju
WJ
Chang
Jo-Shu
JS
Chang
Chia-Che
CC
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D011353:Prodigiosin / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014410:Tumor Stem Cell Assay
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D008156:Luciferases; D011353:Prodigiosin; D017239:Paclitaxel