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Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway

The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hy...

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Autores principales: Luo, Jingyi, Sun, Pengbo, Zhang, Xun, Lin, Guanglan, Xin, Qilei, Niu, Yaoyun, Chen, Yang, Xu, Naihan, Zhang, Yaou, Xie, Weidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704642/
https://www.ncbi.nlm.nih.gov/pubmed/34948132
http://dx.doi.org/10.3390/ijms222413336
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author Luo, Jingyi
Sun, Pengbo
Zhang, Xun
Lin, Guanglan
Xin, Qilei
Niu, Yaoyun
Chen, Yang
Xu, Naihan
Zhang, Yaou
Xie, Weidong
author_facet Luo, Jingyi
Sun, Pengbo
Zhang, Xun
Lin, Guanglan
Xin, Qilei
Niu, Yaoyun
Chen, Yang
Xu, Naihan
Zhang, Yaou
Xie, Weidong
author_sort Luo, Jingyi
collection PubMed
description The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hypoxia, and demonstrated that CANA could significantly inhibit hypoxia-induced metastasis, angiogenesis, and metabolic reprogramming in HCC. At the molecular level, this was accompanied by a reduction in VEGF expression level, as well as a reduction in the epithelial-to-mesenchymal transition (EMT)-related proteins and glycolysis-related proteins. Next, we focused our study particularly on the modulation of HIF-1α by CANA, which revealed that CANA decreased HIF-1α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the AKT/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CANA. Thus, it can be concluded that CANA decreased metastasis, angiogenesis, and metabolic reprogramming in HCC by inhibiting HIF-1α protein accumulation, probably by targeting the AKT/mTOR pathway. Based on our results, we propose that CANA should be evaluated as a new treatment modality for liver cancer.
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spelling pubmed-87046422021-12-25 Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway Luo, Jingyi Sun, Pengbo Zhang, Xun Lin, Guanglan Xin, Qilei Niu, Yaoyun Chen, Yang Xu, Naihan Zhang, Yaou Xie, Weidong Int J Mol Sci Article The microenvironment plays a vital role in tumor progression, and hypoxia is a typical microenvironment feature in nearly all solid tumors. In this study, we focused on elucidating the effect of canagliflozin (CANA), a new class of antidiabetic agents, on hepatocarcinoma (HCC) tumorigenesis under hypoxia, and demonstrated that CANA could significantly inhibit hypoxia-induced metastasis, angiogenesis, and metabolic reprogramming in HCC. At the molecular level, this was accompanied by a reduction in VEGF expression level, as well as a reduction in the epithelial-to-mesenchymal transition (EMT)-related proteins and glycolysis-related proteins. Next, we focused our study particularly on the modulation of HIF-1α by CANA, which revealed that CANA decreased HIF-1α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the AKT/mTOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CANA. Thus, it can be concluded that CANA decreased metastasis, angiogenesis, and metabolic reprogramming in HCC by inhibiting HIF-1α protein accumulation, probably by targeting the AKT/mTOR pathway. Based on our results, we propose that CANA should be evaluated as a new treatment modality for liver cancer. MDPI 2021-12-11 /pmc/articles/PMC8704642/ /pubmed/34948132 http://dx.doi.org/10.3390/ijms222413336 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Luo, Jingyi
Sun, Pengbo
Zhang, Xun
Lin, Guanglan
Xin, Qilei
Niu, Yaoyun
Chen, Yang
Xu, Naihan
Zhang, Yaou
Xie, Weidong
Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway
title Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway
title_full Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway
title_fullStr Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway
title_full_unstemmed Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway
title_short Canagliflozin Modulates Hypoxia-Induced Metastasis, Angiogenesis and Glycolysis by Decreasing HIF-1α Protein Synthesis via AKT/mTOR Pathway
title_sort canagliflozin modulates hypoxia-induced metastasis, angiogenesis and glycolysis by decreasing hif-1α protein synthesis via akt/mtor pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704642/
https://www.ncbi.nlm.nih.gov/pubmed/34948132
http://dx.doi.org/10.3390/ijms222413336
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