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 αB (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 = 0.001, recurrence-free survival (RFS) p = 0.003]. Elevated hazard ratios (HR) were estimated with regard to OS (HR = 2.11, 95% CI 1.10-4.06) and RFS (HR = 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 anti-
cancer 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.