Abstract
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.
Highlights
Renal cell carcinoma (RCC) denotes cancer originating from the renal epithelium and accounts for >90% of cancers in the kidney
The computational simulation by gene set enrichment analysis (GSEA) software demonstrated that the expression of the mTORC1 gene set, which putatively reflects the status of mTORC activity, inversely correlates with the inositol monophosphatase 2 (IMPA2) levels in metastatic or nonmetastatic clear cell renal cell carcinoma (ccRCC) (Figure 1B)
The Chi-square test showed that the signature that combines low-level IMPA2 and high-level mTORC1 gene set expression is extensively detected in ccRCC derived from male patients who are classified as having higher pathologic T status (T3 and T4), pathologic M1, higher pathologic stage (III and IV) or higher neoplasm grade (G3 and G4) (Table S2)
Summary
Renal cell carcinoma (RCC) denotes cancer originating from the renal epithelium and accounts for >90% of cancers in the kidney. CcRCC is the most common subtype (approximately 75%) and accounts for the majority of deaths related to kidney cancer [2]. Multitargeted receptor tyrosine kinase inhibitors pazopanib and sunitinib have been developed as first-line therapies for metastatic ccRCC via inhibiting the activity of vascular endothelial growth factor and mechanistic target of rapamycin (mTOR), referred to as the mammalian target of rapamycin and belonging to a member of the phosphatidylinositol 3-kinase (PI3K)-related protein kinases, but the treatment response is varied, and most cancers eventually progress [4]. A recent report demonstrated that lithium directly inhibits the enzyme activity of IMPA1, not IMPA2, in the cell-based assays [8]. Male transgenic mice with IMPA2 knockout exhibited a lithium-resistant phenotype [12]. These findings demonstrated that IMPA1 and IMPA2 exhibit a different response to lithium treatment and have distinct biological functions. Further experiments are still needed to explore the comprehensive mechanism by which IMPA2 downregulation drives ccRCC metastasis
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