Journal article
PRIMA-1 induces apoptosis by inhibiting JNK signaling but promoting the activation of Bax
Biochemical and biophysical research communications, Vol.352(1), pp.203-212
2007
Handle:
https://hdl.handle.net/2376/112520
PMID: 17113036
Abstract
The p53 protein plays a major role in the maintenance of genome stability in mammalian cells. Mutations of p53 occur in over 40% of breast cancers and are indicative of tumor resistance to chemotherapeutic agents. Recently, there has been a high degree of interest in pharmacological approaches for restoring the normal function to mutant p53. The low molecular weight compound p53 reactivation and induction of massive apoptosis (PRIMA-1) was shown to induce cytotoxic effects and apoptosis in human tumor cells with mutant p53. Here, we studied the molecular mechanisms of PRIMA-1-induced apoptosis in human breast cancer cells with p53 mutations such as MDA-231 and GI-101A as compared to MCF-7 cells. We show that PRIMA-1 selectively induces apoptosis in human breast cancer cells MDA-231 and GI-101A compared to the MCF-7. This effect was paralleled by an increase in total p53 level in the nucleus and the induction of its phosphorylation at Ser-15 site. Using the chromatin immunoprecipitation (ChIP) assays, we show that PRIMA-1 restored p53 DNA binding activity to the promoters of the proapoptotic genes such as Bax and PUMA, but inhibited the binding activity to the promoters of the MAP4K4 gene. Knockdown of p53 protein in breast cancer cells using siRNA followed by PRIMA-1 treatment resulted in decline of Bax and PUMA proteins expression. Cell incubation with either PRIMA-1 or SP600125 (c-Jun NH
2-terminal kinase inhibitor) resulted in the abrogation of adriamycin-induced c-Jun NH
2-terminal kinase (JNK) activation, whereas Bax activation was not inhibited. We conclude that both Bax and PUMA but not JNK signaling are involved in PRIMA-1-induced apoptosis in breast cancer cells with p53 mutation.
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Details
- Title
- PRIMA-1 induces apoptosis by inhibiting JNK signaling but promoting the activation of Bax
- Creators
- Tao Wang - Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, USAKyunghee Lee - Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, USAAbdur Rehman - Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, USASayed S Daoud - Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, USA
- Publication Details
- Biochemical and biophysical research communications, Vol.352(1), pp.203-212
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- Elsevier Inc
- Identifiers
- 99900547420601842
- Language
- English
- Resource Type
- Journal article