TRPC5‑induced autophagy promotes the TMZ‑resistance of glioma cells via the CAMMKβ/AMPKα/mTOR pathway.

Abstract

Temozolomide (TMZ) is the first choice chemotherapy agent against glioblastoma, but the TMZ chemotherapy resistance has restricted the clinical application. Although autophagy is considered an adaptive response for cell survival under the pressure of chemotherapy and associated with chemotherapy resistance, its initiator and the precise molecular mechanism remains unknown. In the present study, it was determined that TMZ increases the transient receptor potential cation channel subfamily C member 5 (TRPC5) protein expression and the basal autophagy level, and the upregulation of autophagy is mediated by TRPC5 in glioma cells. Additionally, knockdown of TRPC5 upregulated the chemotherapy sensitivity in vitro and in vivo. Furthermore, TRPC5‑small interfering RNA and pharmacological inhibition indicated that the Ca2+/calmodulin dependent protein kinase β (CaMKKβ)/AMP‑activated protein kinase α (AMPKα)/mechanistic target of rapamycin kinase (mTOR) pathway mediates cell survival autophagy during TMZ treatment. In addition, TMZ‑resistant U87/TMZ cells retained a high basal autophagy level, while silence of TRPC5 expression or inhibition of autophagy reversed TMZ resistance. Thus, the present study revealed that TRPC5, an initiator of autophagy, upregulated TMZ resistance via the CaMKKβ/AMPKα/mTOR pathway and this indicated a novel therapeutic site for drug resistance in glioma chemotherapy.

• Authors: Yan Zou, Mu Chen, Shuai Zhang, Zeng'li Miao, Jing Wang, Xiao'jie Lu, Xu'dong Zhao
• Journal: Oncology reports (Oncol Rep) Vol. 41 Issue 6 Pg. 3413-3423 (Jun 2019) ISSN: 1791-2431 [Electronic] Greece
• PMID: 30942446 (Publication Type: Journal Article)

Chemical References

• RNA, Small Interfering
• TRPC Cation Channels
• TRPC5 protein, human
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• AMP-Activated Protein Kinases
• PRKAA1 protein, human
• Temozolomide

Topics

• AMP-Activated Protein Kinases (genetics)
• Animals
• Autophagy (drug effects)
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (genetics)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Glioma (drug therapy, genetics, pathology)
• Humans
• Mice
• RNA, Small Interfering (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (genetics)
• TRPC Cation Channels (antagonists & inhibitors, genetics)
• Temozolomide (administration & dosage)
• Xenograft Model Antitumor Assays