Translational implications of endoplasmic reticulum stress response (ERSR) in glioblastoma chemoresistance

Abstract

INTRODUCTION: Temozolomide (TMZ) resistance is a major cause of treatment failure for glioblastoma multiforme (GBM). Endoplasmic reticulum stress response (ERSR) is a normal cellular process that has recently been found to confer TMZ-resistance in GBM. We studied the effect of inhibition of one of the ERSR proteins in the treatment of TMZ-resistant GBM and investigated the underlying molecular mechanisms. MATERIAL AND METHOD: Our previous work had identified the upregulation of prolyl 4-hydroxylase, beta polypeptide (P4HB), an ERSR protein, in TMZ-resistant GBM cells. We further studied the in vitro and in vivo effects of P4HB inhibition using RNA interference techniques. Changes in related ERSR pathways were investigated. Its clinical significance was explored by studying clinical GBM specimens. RESULTS: Inhibition of P4HB resensitized TMZ-resistant GBM cells to a rechallenge of TMZ both in vitro and in an in vivo model of subcutaneous GBM xenografts. The effect was mediated through caspases-dependent apoptosis, and the PERK arm of the ERSR pathways. P4HB was detectable in rodent serum, and was upregulated in a small clinical cohort of TMZ-resistant recurrent GBM. CONCLUSION: P4HB may serve as a predictor of de novo treatment response to TMZ, a serological marker of acquired chemoresistance, and a potential therapeutic target. Targeting the ERSR is a promising approach for the treatment of chemoresistant GBM. Its implications in the development of other treatments such as hyperoxia will be discussed.