Abstract
Malignant gliomas recur even after extensive surgery and chemo‐radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against gliomas, the effects last only a few months and drug resistance develops thereafter in many cases. It has been acknowledged that glioma cells respond to TMZ treatment by undergoing G2/M arrest, but not apoptosis. Here we demonstrate a phase‐specific chemotherapy resistance due to cellular prion protein (PrPc) in human glioma cells upon TMZ treatment. TMZ‐induced G2/M‐arrested cultures show an upregulation of PrPc expression and are more resistant, whereas G1/S‐phase cells that show decreased levels of PrPc are more sensitive to apoptosis. Furthermore, an investigation into the biological significance of PrPc association with par‐4 provided the first evidence of a relationship between the endogenous levels of PrPc and the resistance of glioma cells to the apoptotic effects of TMZ. Upon TMZ treatment, PrPc exerts its antiapoptotic activity by inhibiting PKA‐mediated par‐4 phosphorylation that are important for par‐4 activation, nuclear entry and initiation of apoptosis. In context with cell cycle‐dependent responses to chemotherapy, the data from this study suggest the possibility of exploiting the PrPc‐dependent pathway to improve the efficacy of TMZ‐based regimen for patients with gliomas.