The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

被引:26
作者
Craik, A. C. [1 ]
Veldhoen, R. A. [1 ]
Czernick, M. [1 ]
Buckland, T. W. [1 ]
Kyselytzia, K. [1 ]
Ghosh, S. [2 ]
Lai, R. [3 ]
Damaraju, S. [3 ,4 ]
Underhill, D. A. [2 ,5 ]
Mackey, J. R. [2 ,4 ]
Goping, I. S. [1 ,2 ]
机构
[1] Univ Alberta, Dept Biochem, Sch Mol & Syst Med, Edmonton, AB T6G 2H7, Canada
[2] Univ Alberta, Dept Oncol, Sch Canc Engn & Imaging Sci Med, Edmonton, AB T6G 2H7, Canada
[3] Univ Alberta, Dept Lab Med & Pathol, Sch Clin & Lab Sci, Edmonton, AB T6G 2H7, Canada
[4] Cross Canc Inst, Alberta Hlth Serv, PolyomX Program, Edmonton, AB T6G 1Z2, Canada
[5] Univ Alberta, Dept Med Genet, Sch Human Dev, Edmonton, AB T6G 2H7, Canada
关键词
Bad; taxane; paclitaxel; docetaxel; apoptosis; breast cancer; CELL-SURVIVAL; BH3; DOMAIN; EXPRESSION PATTERNS; MAMMARY-GLAND; MITOTIC BLOCK; APOPTOSIS; PHOSPHORYLATION; BCL-2; DEATH; PACLITAXEL;
D O I
10.1038/onc.2010.272
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Antimitotic agents such as taxanes (paclitaxel and docetaxel) have greatly advanced the treatment of breast cancer, although variable patient response and drug toxicity are major limitations. Lack of validated predictive markers for taxane responsiveness precludes a priori identification of patients who are most likely to respond to treatment; thus, a subset of patients endure toxic side effects with marginal benefit. Mechanistic insights into taxane therapeutic activity may lead to rational therapeutic improvements. In this paper we report that the proapoptotic BH3-only protein Bad has a major role in taxane-induced cell death in vitro, and clinically is a prognostic indicator for overall survival of breast cancer patients after adjuvant taxane chemotherapy. Unexpectedly, Bad did not induce the mitochondrial apoptotic machinery in response to taxane treatment. Instead, Bad indirectly facilitated cell death by stimulating cellular proliferation. As dividing cells are the targets of taxane therapy, Bad-stimulated proliferation may be a marker of taxane sensitivity. Our studies indicate that quantification of Bad protein levels may have value as a diagnostic tool. They also suggest that cells expressing Bad are more sensitive to taxanes because of their altered cell cycle dynamics and reveal a clinically relevant proliferative role of Bad in breast cancer. Oncogene (2010) 29, 5381-5391; doi: 10.1038/onc.2010.272; published online 5 July 2010
引用
收藏
页码:5381 / 5391
页数:11
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