HtrA1 sensitizes ovarian cancer cells to cisplatin‐induced cytotoxicity by targeting XIAP for degradation

Abstract

HtrA1, a member of serine protease family, has been previously found to be involved in resistance to chemotherapy in ovarian cancer although the underlying mechanism is not clear. Using mixture-based oriented peptide library approach, we previously identified X-linked inhibitor of apoptosis protein (XIAP), a member of the inhibitor of apoptosis proteins (IAPs) family as a potential substrate of HtrA1. The aim of this work is to investigate the link between HtrA1 and XIAP proteins and their relationships with chemoresistance in ovarian cancer. Our results showed that recombinant XIAP was degraded by purified wild type HtrA1 but not mutant HtrA1 in vitro. Consistent with the in vitro data, co-immunoprecipitation assays showed that HtrA1 and XIAP formed a protein complex in vivo. Ectopic expression of HtrA1 led to decreased level of XIAP in OV167 and OV202 ovarian cancer cells, while knockdown of HtrA1 resulted in increased level of XIAP in SKOV3 ovarian cancer cells. Furthermore, over-expression of HtrA1 in OV202 cells promoted cell sensitivity to cisplatin-induced apoptosis which could be reversed by increased expression of XIAP. The cleavage of XIAP induced by HtrA1 was enhanced by cisplatin treatment. Taken together, our experiments have identified XIAP as a novel substrate of HtrA1 and the degradation of XIAP by HtrA1 contributes to cell response to chemotherapy, suggesting that restoring the expression of HtrA1 may be a promising treatment strategy for ovarian cancer.

Divergent Roles of PAX2 in the Etiology and Progression of Ovarian Cancer

“…Therefore, PAX2 may confer or inhibit tumor progression at least partially through differential regulation of COX2 and/or HTRA1, depending on the tumor context. This investigation identified novel targets dysregulated by PAX2 (i.e., COX2 and HTRA1), both of which are involved in cell proliferation (40,45). Although apoptotic induction was enhanced by PAX2 in STOSE cells, no apparent apoptosis was evident in STOSE tumors, where PAX2 promoted proliferation.…”

“…6C, is the regulation of Htra1 by PAX2 in these tumors. HTRA1 is a putative tumor suppressor gene that is downregulated in ovarian cancers (39) and enhances chemosensitivity by targeting the antiapoptotic protein XIAP for degradation (40). Downregulation of HTRA1 enhanced peritoneal dissemination in a xenograft study by increasing phosphorylation of EGFR, AKT, and ERK1/2 (22).…”

HtrA1 resensitizes multidrug-resistant hepatocellular carcinoma cells by targeting XIAP

“…Our previous study had also found that the level of HtrA1 protein in hepatoma carcinoma cells, especially the cells in a later stage, was evidently lower than that in normal hepatic tissue, and HtrA1 was negatively correlated with chemotherapy resistance [10]. Even more, high HtrA1 expression enhances the sensibility of tumor cells to chemotherapy [9,11,12].…”

Structural insights into the activation mechanisms of human HtrA serine proteases

“…HtrA1 is ubiquitously expressed among human tissues however its expression level is tissue- It has been demonstrated that HtrA1 is involved in induction of cell death via apoptosis and anoikis. The mechanism by which HtrA1 induces programmed cell death is not fully understood but was found to be dependent on the proteolytic activity of the protease [13,14]. He et al [13] showed that HtrA1-mediated apoptosis is triggered by degradation of XIAP protein, a member of the IAPs.…”

“…The mechanism by which HtrA1 induces programmed cell death is not fully understood but was found to be dependent on the proteolytic activity of the protease [13,14]. He et al [13] showed that HtrA1-mediated apoptosis is triggered by degradation of XIAP protein, a member of the IAPs. Implication of HtrA1 in anoikis is associated with modulation of the epidermal growth factor receptor (EGFR)/Akt signaling pathway.…”