Although
mTOR inhibitors have been approved as first-line
therapy for treating metastatic
clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. The objective of this study was to estimate if
inositol monophosphatase 2 (IMPA2) downregulation refers to a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Gene set enrichment analysis predicted a significant activation of
mTORC1 in the metastatic ccRCC with IMPA2 downregulation. Transcriptional profiling of IMPA2 and mTORC1-related gene set revealed significantly inverse correlation in ccRCC tissues. 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 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. Our findings indicated 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.