TRPC5-Induced Autophagy Promotes The TMZ-Resistance Of Glioma Cells Via CAMMK?/AMPK?/mTOR Pathway

Temozolomide is the first choice chemotherapy agent against glioblastoma,but the TMZ chemotherapy resistance has restricted the clinical application.Although autophagy is believed as an adaptive response for cell survival under pressure of chemotherapy and related to chemotherapy resistance,its precise molecular mechanism remains unclear.In this research,we find that temozolomide increases the TRPC5 expression and the basal autophagy level,and the upregulation of autophagy is mediated by TRPC5 in glioma cells.Knockdown of TRPC5 up-regulates the chemotherapy sensitivity in vitro and in vivo.Furthermore,TRPC5-siRNA and pharmacological inhibition indicated that the CaMKK?/AMPK?/mTOR pathway mediates cyto-survival autophagy during Temozolomidetreatment.Moreover,Temozolomide-resistant U87/TMZ cells retained a high basal autophagy level,while silence of TRPC5 expression or inhibition of autophagy reversed the Temozolomide resistance.Thus,our study revealed TRPC5,an initiator of autophagy,up-regulated the TMZ resistance via CaMKK?/AMPK?/mTOR pathway and this suggested a novel therapeutic site for drug resistance in glioma chemotherapy.