P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism.
P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism.
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DOI：
10.1038/onc.2011.134
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发表时间：
2011-10-13
期刊：
影响因子：
8
通讯作者：
Tsang, B. K.
中科院分区：
文献类型：
--
作者：
Al-Bahlani, S.;Fraser, M.;Wong, A. Y. C.;Sayan, B. S.;Bergeron, R.;Melino, G.;Tsang, B. K.
P73在一些癌细胞的药物诱导凋亡中发挥重要作用，但其在卵巢癌（OVCA）化疗敏感性调节中的作用尚不清楚。此外，p73介导的细胞凋亡的解除是否以及如何导致顺铂（CDDP）治疗的耐药尚不清楚。本研究表明，在化疗敏感细胞（OV2008和A2780s）和耐药细胞（C13*和A2780cp）以及另一种化疗耐药细胞（Hey）中，TAp73α过表达增强了cddp诱导的PARP切割和凋亡；相反，ΔNp73α过表达的影响是可变的。P73α下调可减弱cddp诱导的OV2008细胞PUMA和NOXA上调及凋亡。CDDP降低了OV2008中p73α稳态蛋白水平，但在C13*中没有，尽管mRNA表达相同。cddp诱导的p73α下调是通过calpain依赖通路介导的。在OV2008细胞中，CDDP诱导calpain活化并增强其与p73α的胞质相互作用和共定位，而C13*细胞则没有。CDDP增加了OV2008细胞内钙浓度（[Ca2+]i），但没有增加C13*，而环吡唑酸（CPA），一种Ca2+- atp酶抑制剂，在两种细胞类型中引起这种反应和calpain激活，p73α加工和凋亡。在OV2008细胞中，cddp诱导的[Ca2+]i增加不受细胞外Ca2+消除的影响，但这种增加被细胞内Ca2+储存的消耗所减弱，这表明细胞内Ca2+储存的动员可能参与其中。这些发现表明，p73α及其通过Ca2+介导的calpain通路的调控参与了CDDP诱导的OVCA细胞凋亡，Ca2+/calpain/p73信号的失调可能是CDDP耐药的部分病理生理机制。了解化疗耐药的细胞和分子机制将指导化疗耐药OVCA治疗的有效策略的发展。
P73 is important in drug-induced apoptosis in some cancer cells, yet its role in the regulation of chemosensitivity in ovarian cancer (OVCA) is poorly understood. Furthermore, if and how the deregulation of p73-mediated apoptosis confers resistance to cisplatin (CDDP) treatment is unclear. Here we demonstrate that TAp73α over-expression enhanced CDDP-induced PARP cleavage and apoptosis in both chemosensitive (OV2008 and A2780s) and their resistant counterparts (C13* and A2780cp) and another chemoresistant OVCA cells (Hey); in contrast, the effect of ΔNp73α over-expression was variable. P73α downregulation attenuated CDDP-induced PUMA and NOXA upregulation and apoptosis in OV2008 cells. CDDP decreased p73α steady-state protein levels in OV2008, but not in C13*, although the mRNA expression was identical. CDDP-induced p73α downregulation was mediated by a calpain-dependent pathway. CDDP induced calpain activation and enhanced its cytoplasmic interaction and co-localization with p73α in OV2008, but not C13* cells. CDDP increased the intracellular calcium concentration ([Ca2+]i) in OV2008 but not C13* whereas cyclopiazonic acid (CPA), a Ca2+-ATPase inhibitor, caused this response and calpain activation, p73α processing and apoptosis in both cell types. CDDP-induced [Ca2+]i increase in OV2008 cells was not effected by the elimination of extracellular Ca2+, but this was attenuated by the depletion of internal Ca2+ store, indicating that mobilization of intracellular Ca2+] stores was potentially involved. These findings demonstrate that p73α and its regulation by the Ca2+-mediated calpain pathway are involved in CDDP-induced apoptosis in OVCA cells and that dysregulation of Ca2+/calpain/p73 signaling may in part be the pathophysiology of CDDP resistance. Understanding the cellular and molecular mechanisms of chemoresistance will direct the development of effective strategies for the treatment of chemoresistant OVCA.
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