IMPA2 Downregulation Enhances mTORC1 Activity and Restrains Autophagy Initiation in Metastatic Clear Cell Renal Cell Carcinoma

Autor: Kuan-Chou Chen, Hui Yu Lin, Yuan Feng Lin, Hsun-Hua Lee, Jing-Quan Zheng, Che-Hsuan Lin, Chia-Hao Kuei
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of Clinical Medicine
Volume 9
Issue 4
Journal of Clinical Medicine, Vol 9, Iss 956, p 956 (2020)
ISSN: 2077-0383
DOI: 10.3390/jcm9040956
Popis: Background: Although mTOR inhibitors have been approved as a first-line therapy for treating metastatic clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. We investigated whether IMPA2 downregulation predicts a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Methods: An in silico Gene Set Enrichment Analysis (GSEA) was used to estimate correlation between the transcriptional profile of IMPA2 and mTORC1 gene set in ccRCC patients. Kaplan-Meier analysis was used to estimate the prognostic significance of the signature that combines low-level IMPA2 and high-level mTORC1 gene set expression ccRCC patients. The cellular migration and lung colony-forming assays were performed to evaluate therapeutic effectiveness of mTOR inhibition on the metastatic ccRCC cells with IMPA2 downregulation. Findings: The signature that combines low-level IMPA2 and high-level mTORC1 gene set expression correlated with a poorer prognosis in ccRCC patients. Whereas the enforced expression of exogenous IMPA2 inhibited the phosphorylation of Akt/mTORC1, artificially silencing IMPA2 led to increased phosphorylation of Akt/mTORC1 in ccRCC cells. The pharmaceutical inhibition of mTORC1 activity by rapamycin reinforced the autophagy initiation but suppressed the cellular migration and lung metastatic abilities of IMPA2-silenced ccRCC cells. In contrast, blocking autophagosome formation with 3-methyladenine rescued the mitigated metastatic potential in vitro and in vivo in IMPA2-overexpressing ccRCC cells. Interpretation: Our findings revealed that IMPA2 downregulation negatively activates mTORC1 activity and could be a biomarker for guiding the use of mTOR inhibitors or autophagy inducers to combat metastatic ccRCC in the clinic. Funding Statement: This study was supported by the Ministry of Science and Technology, Taiwan (MOST 108-2320-B-038-017-MY3) to Yuan-Feng Lin and Chia-Hao Kuei (MOST 108-2314-B-567-001) Cardinal Tien Hospital, Xindian District, New Taipei City, Taiwan (CTH108A-2A01) to Chia-Hao Kuei. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Care and Use Committee at Taipei Medical University.
Databáze: OpenAIRE
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