Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53.
Undecylprodigiosin (UP) is a bacterial bioactive metabolite produced by Streptomyces and Serratia. In this study, we explored the anticancer effect of UP. Human breast carcinoma cell lines BT-20, MCF-7, MDA-MB-231 and T47D and one nonmalignant human breast epithelial cell line, MCF-10A, were tested in this study. We found that UP exerted a potent cytotoxicity against all breast carcinoma cell lines in a dose- and time-dependent manner. In contrast, UP showed limited toxicity to MCF-10A cells, indicating UP's cytotoxic effect is selective for malignant cells. UP's cytotoxic effect was due to apoptosis, as confirmed by positive TUNEL signals, annexin V-binding, caspase 9 activation and PARP cleavage. Notably, UP-induced apoptosis was blocked by the pan-caspase inhibitor z-VAD.fmk, further indicating the involvement of caspase activity. Moreover, UP caused a marked decrease of the levels of antiapoptotic BCL-X(L), Survivin and XIAP while enhancing the levels of proapoptotic BIK, BIM, MCL-1S and NOXA, consequently favoring induction of apoptosis. Additionally, we found that cells with functional p53 (MCF-7, T47D) or mutant p53 (BT-20, MDA-MB-231) were both susceptible to UP's cytotoxicity. Importantly, UP was able to induce apoptosis in MCF-7 cells with p53 knockdown by RNA interference, confirming the dispensability of p53 in UP-induced apoptosis. Overall, our results establish that UP induces p53-independent apoptosis in breast carcinoma cells with no marked toxicity to nonmalignant cells, raising the possibility of its use as a new chemotherapeutic drug for breast cancer irrespective of p53 status.
Ho
Tsing-Fen
TF
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
Ma
Chieh-Ju
CJ
Lu
Chien-Hsing
CH
Tsai
Yo-Ting
YT
Wei
Yu-Hong
YH
Chang
Jo-Shu
JS
Lai
Jun-Kai
JK
Cheuh
Pin-Ju
PJ
Yeh
Chi-Tai
CT
Tang
Pin-Chi
PC
Tsai Chang
Jinghua
J
Ko
Jiunn-Liang
JL
Liu
Fu-Shing
FS
Yen
Hungchen E
HE
Chang
Chia-Che
CC
D017304:Annexin A5 / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000188:drug therapy*; D053453:Caspase 9 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D011353:Prodigiosin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012706:Serratia marcescens / Q000737:chemistry; D000077022:Survivin; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000378:metabolism; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism
D017304:Annexin A5; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C096820:BIK protein, human; C107489:BIRC5 protein, human; D000072224:Bcl-2-Like Protein 11; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; C047347:undecylprodigiosin; D011065:Poly(ADP-ribose) Polymerases; D053453:Caspase 9; D011353:Prodigiosin