HSPA6 maintains IMPDH2 phosphorylation to regulate GTP synthesis for driving radioresistance of glioblastoma stem cells

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) promote radioresistance and therapeutic failure, yet the underlying mechanisms remain unclear. Here, we show that heat shock protein HSPA6 promotes GSC radioresistance by enhancing GTP synthesis. HSPA6 is induced by irradiation and reduces GSC sensitivity to radiotherapy. HSPA6 interacts with and activates IMPDH2, a key rate-limiting enzyme in purine biosynthesis, thereby promoting GTP synthesis, reducing DNA damage, and enhancing radioresistance. Mechanistically, HSPA6 recruits ROCK2 to phosphorylate and activate IMPDH2 at S416. Pharmacological inhibition of HSPA6 and IMPDH2 combined with irradiation significantly improves survival in mice bearing GBM. Our study uncovers the crucial role of HSPA6/IMPDH2-mediated GTP synthesis in GSC radioresistance and suggests that targeting this axis may improve radiotherapy efficacy for GBM.

Keywords: CP: Cancer; CP: Genomics; GTP synthesis; glioblastoma; glioblastoma stem cells; heat shock protein family A member 6; radioresistance.