High expression of crystallin αB represents an independent molecular marker for unfavourable ovarian cancer patient outcome and impairs TRAIL‐ and cisplatin‐induced apoptosis in human ovarian cancer cells

Abstract

Dysregulated apoptotic pathways are regarded as major reasons for chemoresistance development as a particular challenge in ovarian cancer therapy. In search of molecular factors affecting human ovarian cancer cell apoptosis and, consequently, patient survival, we examined tumors of 103 platinum-/taxane-treated ovarian cancer patients by mRNA-array hybridization, qPCR, and immunohistochemistry. We identified high expression of crystallin aB (CRYAB), a proposed negative regulator of tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. By Kaplan Meier analysis, this factor turned out to be significantly associated with poor patient outcome [overall survival (OS) p 5 0.001, recurrence-free survival (RFS) p 5 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR 5 2.11, 95% CI 1.10-4.06) and RFS (HR 5 1.92, 95% CI 1.07-3.47) in multivariable analyses. These associations were confirmed in independent, publicly available mRNA data comprising 431 patients for OS (p < 0.001) and 413 for RFS (p < 0.001) . Our findings were validated by studying apoptotic events in cultured human ovarian cancer cells which were stably transfected to express elevated CRYAB levels. These data emphasized the crucial role of CRYAB in human ovarian cancer biology since TRAIL-as well as cisplatin-induced apoptosis was significantly impaired as a function of enhanced CRYAB expression. Taken together, we identified CRYAB as an independent biomarker for unfavourable outcome of human ovarian cancer patients. Since TRAIL is currently tested as anticancer drug and large proportions of the present patient cohort displayed low CRYAB levels in their tumors, CRYAB may enable the selection of patient subgroups benefiting most from TRAIL-containing therapy.Epithelial ovarian cancer is the fifth most common cause for cancer-related death in women in Western societies and has the highest relative mortality among gynecological cancers. 1,2Approximately 75% of patients are diagnosed at an advanced FIGO stage (III or IV). These patients display a 5-year survival rate of less than 40%.1,3 The currently recommended standard postoperative chemotherapy is platinum-taxanebased. Although initial response rates are often high, most of the patients relapse and develop chemoresistance with fatal outcome. 4 Besides decreased response to DNA damage, increased tumor cell survival largely mediated through dysregulation of apoptotic pathways is regarded as one major reason for chemoresistance. 5,6 This prompted us to search for molecular factors affecting apoptotic pathways in human ovarian cancer, and consequently, patient survival.Differential mRNA expression analysis in tumor specimens of a clinically homogenous cohort of 103 human ovarian cancer patients disclosed CRYAB, a member of the highly

Heat shock factor 1 induces crystallin-αB to protect against cisplatin nephrotoxicity

“…This observation is consistent with the antiapoptotic function of CryAB previously reported by others (13,15,22). A recent study by Volkmann et al (34) further showed that overexpression of CryAB protected against cisplatin-induced apoptosis in human ovarian cancer cells. CryAB has been shown to bind and sequester proapoptotic proteins, such as Bax (13,15).…”

The Dynamic Duo of Small Heat Proteins and IFs Maintain Cell Homeostasis, Resist Cellular Stress and Enable Evolution in Cells and Tissues

“…It binds directly to TP53 (Watanabe et al 2009 ;Liu et al 2007 ). In the canonical wnt-signalling pathway, αB-crystallin binds to the E-cadherin-β-catenin complex to maintain a membrane location for the complex ) Recent data suggest that αB-crystallin could regulate systemic expansion of IMCs through a cell-intrinsic mechanism (Dieterich et al 2013 ) Metastasis The direct involvement of αB-crystallin in the regulation of the cell cycle combined with the fact that the overexpression of αB-crystallin itself can complete the transformation process in immortalized human mammary epithelial cells (Moyano et al 2006 ) CRYAB is a marker of poor prognosis in cancer (Moyano et al 2006 ;Ivanov et al 2008 ) and its ability to prevent apoptosis contributes to the aggressiveness of these and other tumours (Goplen et al 2010 ;Volkmann et al 2012 ). CRYAB expression in breast cancer is regulated by both TP53 and Ets1 (Bosman et al 2010 ).…”

“…CRYAB expression in breast cancer is regulated by both TP53 and Ets1 (Bosman et al 2010 ). αB-crystallin is associated signifi cantly with ovarian (Volkmann et al 2012 ), glioblastoma (Goplen et al 2010 ) and hepatocellular carcinomas (Tang et al 2009 ). αB-crystallin in combination with HSPB2 promote tumour vascularization (Dimberg et al 2008 ) via a VEGF-A based mechanism (Kase et al 2010 ).…”

Role of Small Heat Shock Protein HspB5 in Cancer

“…Consequently HspB5 can be considered as a biomarker in the diagnosis of breast cancers, especially in those with advanced grade (Ivanov et al 2008 ;Sitterding et al 2008 ;Tsang et al 2012 ). Similarly, high levels of HspB5 are associated with low survival rate in hepatocellular carcinoma (Huang et al 2013 ;Tang et al 2009 ), ovarian carcinoma (Volkmann et al 2013 ), clear cell renal cell carcinoma (Ho et al 2013 ) and head and neck squamous cell carcinoma (van de Schootbrugge et al 2013 ). In non-small-cell lung cancer only the nuclear and not the cytoplasmic localized HspB5 correlated with poor survival (Cherneva et al 2010 ).…”