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Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC

Metabolic reprogramming is a hallmark of human cancer. Cancer cells exhibit enhanced glycolysis, which allows glycolytic intermediates to be diverted into several other biosynthetic pathways, such as serine synthesis. Here, we explored the anti-cancer effects of the pyruvate kinase (PK) M2 inhibitor...

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Autores principales: Wang, Kaixuan, Lu, Hao, Wang, Xinmiao, Liu, Qingxia, Hu, Jinxia, Liu, Yao, Jin, Meihua, Kong, Dexin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239820/
https://www.ncbi.nlm.nih.gov/pubmed/37284309
http://dx.doi.org/10.3389/fphar.2023.1200538
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author Wang, Kaixuan
Lu, Hao
Wang, Xinmiao
Liu, Qingxia
Hu, Jinxia
Liu, Yao
Jin, Meihua
Kong, Dexin
author_facet Wang, Kaixuan
Lu, Hao
Wang, Xinmiao
Liu, Qingxia
Hu, Jinxia
Liu, Yao
Jin, Meihua
Kong, Dexin
author_sort Wang, Kaixuan
collection PubMed
description Metabolic reprogramming is a hallmark of human cancer. Cancer cells exhibit enhanced glycolysis, which allows glycolytic intermediates to be diverted into several other biosynthetic pathways, such as serine synthesis. Here, we explored the anti-cancer effects of the pyruvate kinase (PK) M2 inhibitor PKM2-IN-1 alone or in combination with the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503 in human NSCLC A549 cells in vitro and in vivo. PKM2-IN-1 inhibited proliferation and induced cell cycle arrest and apoptosis, with increased glycolytic intermediate 3-phosphoglycerate (3-PG) level and PHGDH expression. The combination of PKM2-IN-1 and NCT-503 further suppressed cancer cell proliferation and induced G2/M phase arrest, accompanied by the reduction of ATP, activation of AMPK and inhibition of its downstream mTOR and p70S6K, upregulation of p53 and p21, as well as downregulation of cyclin B1 and cdc2. In addition, combined treatment triggered ROS-dependent apoptosis by affecting the intrinsic Bcl-2/caspase-3/PARP pathway. Moreover, the combination suppressed glucose transporter type 1 (GLUT1) expression. In vivo, co-administration of PKM2-IN-1 and NCT-503 significantly inhibited A549 tumor growth. Taken together, PKM2-IN-1 in combination with NCT-503 exhibited remarkable anti-cancer effects through induction of G2/M cell cycle arrest and apoptosis, in which the metabolic stress induced ATP reduction and ROS augmented DNA damage might be involved. These results suggest that the combination of PKM2-IN-1 and NCT-503 might be a potential strategy for the therapy of lung cancer.
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spelling pubmed-102398202023-06-06 Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC Wang, Kaixuan Lu, Hao Wang, Xinmiao Liu, Qingxia Hu, Jinxia Liu, Yao Jin, Meihua Kong, Dexin Front Pharmacol Pharmacology Metabolic reprogramming is a hallmark of human cancer. Cancer cells exhibit enhanced glycolysis, which allows glycolytic intermediates to be diverted into several other biosynthetic pathways, such as serine synthesis. Here, we explored the anti-cancer effects of the pyruvate kinase (PK) M2 inhibitor PKM2-IN-1 alone or in combination with the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503 in human NSCLC A549 cells in vitro and in vivo. PKM2-IN-1 inhibited proliferation and induced cell cycle arrest and apoptosis, with increased glycolytic intermediate 3-phosphoglycerate (3-PG) level and PHGDH expression. The combination of PKM2-IN-1 and NCT-503 further suppressed cancer cell proliferation and induced G2/M phase arrest, accompanied by the reduction of ATP, activation of AMPK and inhibition of its downstream mTOR and p70S6K, upregulation of p53 and p21, as well as downregulation of cyclin B1 and cdc2. In addition, combined treatment triggered ROS-dependent apoptosis by affecting the intrinsic Bcl-2/caspase-3/PARP pathway. Moreover, the combination suppressed glucose transporter type 1 (GLUT1) expression. In vivo, co-administration of PKM2-IN-1 and NCT-503 significantly inhibited A549 tumor growth. Taken together, PKM2-IN-1 in combination with NCT-503 exhibited remarkable anti-cancer effects through induction of G2/M cell cycle arrest and apoptosis, in which the metabolic stress induced ATP reduction and ROS augmented DNA damage might be involved. These results suggest that the combination of PKM2-IN-1 and NCT-503 might be a potential strategy for the therapy of lung cancer. Frontiers Media S.A. 2023-05-22 /pmc/articles/PMC10239820/ /pubmed/37284309 http://dx.doi.org/10.3389/fphar.2023.1200538 Text en Copyright © 2023 Wang, Lu, Wang, Liu, Hu, Liu, Jin and Kong. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Kaixuan
Lu, Hao
Wang, Xinmiao
Liu, Qingxia
Hu, Jinxia
Liu, Yao
Jin, Meihua
Kong, Dexin
Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC
title Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC
title_full Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC
title_fullStr Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC
title_full_unstemmed Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC
title_short Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC
title_sort simultaneous suppression of pkm2 and phgdh elicits synergistic anti-cancer effect in nsclc
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10239820/
https://www.ncbi.nlm.nih.gov/pubmed/37284309
http://dx.doi.org/10.3389/fphar.2023.1200538
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