Contribution of p53-mediated Bax transactivation in theaflavin-induced mammary epithelial carcinoma cell apoptosis
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Theaflavins, the bioactive flavonoids of black tea, have been demonstrated to inhibit proliferation and induce apoptosis in a variety of cancer cells. However, the contribution of p53 in mammary epithelial carcinoma cell apoptosis by theaflavins remains unclear. It has been reported that p53 triggers apoptosis by inducing mitochondrial outer membrane permeabilization through transcription-dependent and -independent mechanisms. Using wild-type and mutant p53-expressing as well as p53-null cells we found a strong correlation between p53 status and theaflavin-induced breast cancer cell apoptosis. Apoptogenic effect was more pronounced in functional p53-expressing cells in which theaflavins raised p53 protein levels that harmonized with Bax up-regulation and migration to mitochondria. However, in the same cells, when p53-mediated transactivation was inhibited by pifithrin-α, theaflavins not only failed to increase transcription but also to induce apoptosis although p53 up-regulation was not altered. In contrast, Bax over-expression restored back theaflavin-induced apoptosis in pifithrin-α-inhibited/dominant-negative p53-expressing cells. Inhibition of Bax by RNA-interference also reduced theaflavin-induced apoptosis. These results not only indicated the requirement of p53-mediated transcriptional activation of Bax but also its role as down-stream effecter in theaflavin-induced apoptosis. Bax up-regulation resulted in mitochondrial transmembrane potential loss and cytochrome c release followed by activation of caspase cascade. In contrast, mitochondrial translocation of p53 and its interaction with Bcl-2 family proteins or activation of caspase-8 could not be traced thereby excluding the involvement of p53-mediated transcription-independent pathways. Together these findings suggest that in breast cancer cells, p53 promotes theaflavin-induced apoptosis in a transcription-dependent manner through mitochondrial death cascade.
KeywordsApoptosis Bax MTP p53 Theaflavins Transactivation
Mitochondrial transmembrane potential
Normal mammary epithelial
We thank Mr. U. Ghosh and Mr. R. Dutta for technical help. This work was supported by research grants from DST, Government of India.
- 4.Kojima K, Konopleva M, McQueen T, O’brien S, Plunkett W, Andreeff M (2006) Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood 108:993–1000PubMedCrossRefGoogle Scholar
- 10.Siddiqui IA, Zaman N, Aziz MH, Reagan-Shaw SR, Sarfaraz S, Adhami VM et al (2006) Inhibition of CWR22Rnu1 tumor growth and PSA secretion in athymic nude mice by green and black teas. Carcinogenesis 4:833–839Google Scholar
- 17.Zhu X, Yu QS, Cutler RG, Culmsee CW, Holloway HW, Lahiri DK et al (2002) Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives. J Med Chem 45:5090–5097PubMedCrossRefGoogle Scholar