P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism

Abstract

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.

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

“…[11][12][13][14][15] It is involved in several biological processes, such as cell death, [16][17][18][19] differentiation, [20][21][22] neuronal stem cell maintenance, [23][24][25][26] the amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…[81][82][83][84] Both p63 and p73 isoforms have been linked to resistance to cisplatinum in ovarian as well as triple-negative breast cancer cells lines. 85,86 Data from human studies are few, but one study found high expression of the p73-dominant negative isoforms (DNp73 and DN'p73) to be associated with platinum resistance in ovarian cancers harbouring TP53 mutations. 87 MDM2 AND MDM4 Although MDM2 and MDM4 execute their oncogenic effects by overexpression, the importance of each protein and lack of redundancy are illustrated by the fact that MDM2 and MDMX (the mouse homologue of MDM4) deletion in mice cause embryonic lethality, the former at the blastula stage and the latter 7-11 days into the gestation period.…”

Calpain-mediated Processing of p53-associated Parkin-like Cytoplasmic Protein (PARC) Affects Chemosensitivity of Human Ovarian Cancer Cells by Promoting p53 Subcellular Trafficking

“…Calpain activation is Ca 2ϩ -dependent, and CDDP increases intracellular Ca 2ϩ levels in chemosensitive OV2008 cells but not in its resistant variant (C13*) (40). Because calpain content is the same in both chemosensitive and resistant OVCA cells (Fig.…”