Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53

Tsing Fen Ho, Chieh Ju Ma, Chien Hsing Lu, Yo Ting Tsai, Yu Hong Wei, Jo-Shu Chang, Jun Kai Lai, Pin Ju Cheuh, Chi Tai Yeh, Pin Chi Tang, Jinghua Tsai Chang, Jiunn Liang Ko, Fu Shing Liu, Hungchen E. Yen, Chia Che Chang

Research output: Contribution to journalArticle

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Abstract

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-XL, 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.

Original languageEnglish
Pages (from-to)318-328
Number of pages11
JournalToxicology and Applied Pharmacology
Volume225
Issue number3
DOIs
Publication statusPublished - 2007 Dec 15

Fingerprint

Cells
Apoptosis
Breast Neoplasms
Cytotoxicity
Cell Line
Toxicity
Serratia
undecylprodigiosin
Caspase Inhibitors
Caspase 9
Annexin A5
MCF-7 Cells
In Situ Nick-End Labeling
Streptomyces
Caspases
Metabolites
RNA Interference
Breast
Epithelial Cells
Chemical activation

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Ho, Tsing Fen ; Ma, Chieh Ju ; Lu, Chien Hsing ; Tsai, Yo Ting ; Wei, Yu Hong ; Chang, Jo-Shu ; Lai, Jun Kai ; Cheuh, Pin Ju ; Yeh, Chi Tai ; Tang, Pin Chi ; Tsai Chang, Jinghua ; Ko, Jiunn Liang ; Liu, Fu Shing ; Yen, Hungchen E. ; Chang, Chia Che. / Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53. In: Toxicology and Applied Pharmacology. 2007 ; Vol. 225, No. 3. pp. 318-328.
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title = "Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53",
abstract = "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-XL, 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.",
author = "Ho, {Tsing Fen} and Ma, {Chieh Ju} and Lu, {Chien Hsing} and Tsai, {Yo Ting} and Wei, {Yu Hong} and Jo-Shu Chang and Lai, {Jun Kai} and Cheuh, {Pin Ju} and Yeh, {Chi Tai} and Tang, {Pin Chi} and {Tsai Chang}, Jinghua and Ko, {Jiunn Liang} and Liu, {Fu Shing} and Yen, {Hungchen E.} and Chang, {Chia Che}",
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Ho, TF, Ma, CJ, Lu, CH, Tsai, YT, Wei, YH, Chang, J-S, Lai, JK, Cheuh, PJ, Yeh, CT, Tang, PC, Tsai Chang, J, Ko, JL, Liu, FS, Yen, HE & Chang, CC 2007, 'Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53', Toxicology and Applied Pharmacology, vol. 225, no. 3, pp. 318-328. https://doi.org/10.1016/j.taap.2007.08.007

Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53. / Ho, Tsing Fen; Ma, Chieh Ju; Lu, Chien Hsing; Tsai, Yo Ting; Wei, Yu Hong; Chang, Jo-Shu; Lai, Jun Kai; Cheuh, Pin Ju; Yeh, Chi Tai; Tang, Pin Chi; Tsai Chang, Jinghua; Ko, Jiunn Liang; Liu, Fu Shing; Yen, Hungchen E.; Chang, Chia Che.

In: Toxicology and Applied Pharmacology, Vol. 225, No. 3, 15.12.2007, p. 318-328.

Research output: Contribution to journalArticle

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T1 - Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53

AU - Ho, Tsing Fen

AU - Ma, Chieh Ju

AU - Lu, Chien Hsing

AU - Tsai, Yo Ting

AU - Wei, Yu Hong

AU - Chang, Jo-Shu

AU - Lai, Jun Kai

AU - Cheuh, Pin Ju

AU - Yeh, Chi Tai

AU - Tang, Pin Chi

AU - Tsai Chang, Jinghua

AU - Ko, Jiunn Liang

AU - Liu, Fu Shing

AU - Yen, Hungchen E.

AU - Chang, Chia Che

PY - 2007/12/15

Y1 - 2007/12/15

N2 - 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-XL, 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.

AB - 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-XL, 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.

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