IMPA2 Downregulation Enhances mTORC1 Activity and Restrains Autophagy Initiation in Metastatic Clear Cell Renal Cell Carcinoma
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 refe...
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| Published in | Journal of clinical medicine Vol. 9; no. 4; p. 956 |
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| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
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30.03.2020
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| Abstract | 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. |
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| AbstractList | 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. 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.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. |
| Author | Zheng, Jing-Quan Lin, Che-Hsuan Lee, Hsun-Hua Chen, Kuan-Chou Kuei, Chia-Hao Lin, Hui-Yu Lin, Yuan-Feng |
| AuthorAffiliation | 2 Department of Urology, Division of Surgery, Cardinal Tien Hospital, Xindian district, New Taipei City 23148, Taiwan 3 Department of Breast Surgery and General Surgery, Division of Surgery, Cardinal Tien Hospital, Xindian district, New Taipei City 23148, Taiwan 4 Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan 6 Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan 8 Department of Otolaryngology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan 5 Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; pplay1028@gmail.com (C.-H.K.); candycarol0227@gmail.com (H.-Y.L.); kaorulei@yahoo.com.tw (H.-H.L.); 16044@s.tmu.edu.tw (J.-Q.Z.); kuanchou@tmu.edu.tw ( |
| AuthorAffiliation_xml | – name: 11 Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23148, Taiwan – name: 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; pplay1028@gmail.com (C.-H.K.); candycarol0227@gmail.com (H.-Y.L.); kaorulei@yahoo.com.tw (H.-H.L.); 16044@s.tmu.edu.tw (J.-Q.Z.); kuanchou@tmu.edu.tw (K.-C.C.) – name: 4 Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan – name: 7 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; cloudfrank@gmail.com – name: 3 Department of Breast Surgery and General Surgery, Division of Surgery, Cardinal Tien Hospital, Xindian district, New Taipei City 23148, Taiwan – name: 8 Department of Otolaryngology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan – name: 12 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan – name: 10 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan – name: 2 Department of Urology, Division of Surgery, Cardinal Tien Hospital, Xindian district, New Taipei City 23148, Taiwan – name: 6 Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan – name: 9 Department of Critical Care Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan – name: 5 Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan |
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| CitedBy_id | crossref_primary_10_1136_jim_2020_001524 crossref_primary_10_1016_j_biopha_2023_114442 crossref_primary_10_1016_j_tranon_2022_101588 crossref_primary_10_1038_s41467_023_40596_0 |
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| SubjectTerms | Autophagy Clinical medicine Enzymes Genes Kidney cancer Kinases Laboratory animals Membranes Metastasis Penicillin Plasmids Proteins |
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| Title | IMPA2 Downregulation Enhances mTORC1 Activity and Restrains Autophagy Initiation in Metastatic Clear Cell Renal Cell Carcinoma |
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