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PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer

Glycolysis has been reported to be critical for cancer stem cells (CSCs), which are associated with tumor chemoresistance, metastasis and recurrence. Thus, selectively targeting glycolytic enzymes may be a potential therapy for ovarian cancer. 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (P...

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Autores principales: Jiang, Yu-xin, Siu, Michelle K. Y., Wang, Jing-jing, Leung, Thomas H. Y., Chan, David W., Cheung, Annie N. Y., Ngan, Hextan Y. S., Chan, Karen K. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837381/
https://www.ncbi.nlm.nih.gov/pubmed/35155224
http://dx.doi.org/10.3389/fonc.2022.748403
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author Jiang, Yu-xin
Siu, Michelle K. Y.
Wang, Jing-jing
Leung, Thomas H. Y.
Chan, David W.
Cheung, Annie N. Y.
Ngan, Hextan Y. S.
Chan, Karen K. L.
author_facet Jiang, Yu-xin
Siu, Michelle K. Y.
Wang, Jing-jing
Leung, Thomas H. Y.
Chan, David W.
Cheung, Annie N. Y.
Ngan, Hextan Y. S.
Chan, Karen K. L.
author_sort Jiang, Yu-xin
collection PubMed
description Glycolysis has been reported to be critical for cancer stem cells (CSCs), which are associated with tumor chemoresistance, metastasis and recurrence. Thus, selectively targeting glycolytic enzymes may be a potential therapy for ovarian cancer. 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), the main source of fructose-2,6-bisphosphate, controls the first committed step in glycolysis. We investigate the clinical significance and roles of PFKFB3 in ovarian cancer using in vitro and in vivo experiments. We demonstrate that PFKFB3 is widely overexpressed in ovarian cancer and correlates with advanced stage/grade and poor outcomes. Significant up-regulation of PFKFB3 was found in ascites and metastatic foci, as well as CSC-enriched tumorspheres and ALDH+CD44+ cells. 3PO, a PFKFB3 inhibitor, reduced lactate level and sensitized A2780CP cells to cisplatin treatment, along with the modulation of inhibitors of apoptosis proteins (c-IAP1, c-IAP2 and survivin) and an immune modulator CD70. Blockade of PFKFB3 by siRNA approach in the CSC-enriched subset led to decreases in glycolysis and CSC properties, and activation of the NF-κB cascade. PFK158, another potent inhibitor of PFKFB3, impaired the stemness of ALDH+CD44+ cells in vitro and in vivo, whereas ectopic expression of PFKFB3 had the opposite results. Overall, PFKFB3 was found to mediate metabolic reprogramming, chemoresistance, metastasis and stemness in ovarian cancer, possibly via the modulation of inhibitors of apoptosis proteins and the NF-κB signaling pathway; thus, suggesting that PFKFB3 may be a potential therapeutic target for ovarian cancer.
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spelling pubmed-88373812022-02-12 PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer Jiang, Yu-xin Siu, Michelle K. Y. Wang, Jing-jing Leung, Thomas H. Y. Chan, David W. Cheung, Annie N. Y. Ngan, Hextan Y. S. Chan, Karen K. L. Front Oncol Oncology Glycolysis has been reported to be critical for cancer stem cells (CSCs), which are associated with tumor chemoresistance, metastasis and recurrence. Thus, selectively targeting glycolytic enzymes may be a potential therapy for ovarian cancer. 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3), the main source of fructose-2,6-bisphosphate, controls the first committed step in glycolysis. We investigate the clinical significance and roles of PFKFB3 in ovarian cancer using in vitro and in vivo experiments. We demonstrate that PFKFB3 is widely overexpressed in ovarian cancer and correlates with advanced stage/grade and poor outcomes. Significant up-regulation of PFKFB3 was found in ascites and metastatic foci, as well as CSC-enriched tumorspheres and ALDH+CD44+ cells. 3PO, a PFKFB3 inhibitor, reduced lactate level and sensitized A2780CP cells to cisplatin treatment, along with the modulation of inhibitors of apoptosis proteins (c-IAP1, c-IAP2 and survivin) and an immune modulator CD70. Blockade of PFKFB3 by siRNA approach in the CSC-enriched subset led to decreases in glycolysis and CSC properties, and activation of the NF-κB cascade. PFK158, another potent inhibitor of PFKFB3, impaired the stemness of ALDH+CD44+ cells in vitro and in vivo, whereas ectopic expression of PFKFB3 had the opposite results. Overall, PFKFB3 was found to mediate metabolic reprogramming, chemoresistance, metastasis and stemness in ovarian cancer, possibly via the modulation of inhibitors of apoptosis proteins and the NF-κB signaling pathway; thus, suggesting that PFKFB3 may be a potential therapeutic target for ovarian cancer. Frontiers Media S.A. 2022-01-28 /pmc/articles/PMC8837381/ /pubmed/35155224 http://dx.doi.org/10.3389/fonc.2022.748403 Text en Copyright © 2022 Jiang, Siu, Wang, Leung, Chan, Cheung, Ngan and Chan 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 Oncology
Jiang, Yu-xin
Siu, Michelle K. Y.
Wang, Jing-jing
Leung, Thomas H. Y.
Chan, David W.
Cheung, Annie N. Y.
Ngan, Hextan Y. S.
Chan, Karen K. L.
PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer
title PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer
title_full PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer
title_fullStr PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer
title_full_unstemmed PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer
title_short PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer
title_sort pfkfb3 regulates chemoresistance, metastasis and stemness via iap proteins and the nf-κb signaling pathway in ovarian cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837381/
https://www.ncbi.nlm.nih.gov/pubmed/35155224
http://dx.doi.org/10.3389/fonc.2022.748403
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