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Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells
OBJECTIVE(S): STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT3 activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mashhad University of Medical Sciences
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9392574/ https://www.ncbi.nlm.nih.gov/pubmed/36033954 http://dx.doi.org/10.22038/IJBMS.2022.64138.14121 |
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author | Tezcanli Kaymaz, Burcin Selvi Gunel, Nur Sogutlu, Fatma Ozates Ay, Neslihan Pinar Baran, Yusuf Gunduz, Cumhur Biray Avci, Cigir |
author_facet | Tezcanli Kaymaz, Burcin Selvi Gunel, Nur Sogutlu, Fatma Ozates Ay, Neslihan Pinar Baran, Yusuf Gunduz, Cumhur Biray Avci, Cigir |
author_sort | Tezcanli Kaymaz, Burcin |
collection | PubMed |
description | OBJECTIVE(S): STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT3 activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing to resistance to TKI nilotinib. To investigate the possible therapeutic effects of targeting STAT3 to overcome nilotinib resistance by evaluating various cellular responses in both sensitive and nilotinib resistant CML cells and to test the hypothesis that energy metabolism modulation could be a mechanism for re-sensitization to nilotinib in resistant cells. MATERIALS AND METHODS: By using RNAi-mediated STAT3 gene silencing, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT mRNA transcripts, STAT3 total, pTyr705, pSer727 protein expression levels, and metabolic activity as energy metabolism was determined in CML model K562 cells, in vitro. RESULTS: Targeting STAT3 sensitized both parental and especially nilotinib resistant cells by decreasing leukemic cell survival; inducing leukemic cell apoptosis, and decreasing STAT3 mRNA and protein expression levels. Besides, cell energy phenotype was modulated by switching energy metabolism from aerobic glycolysis to mitochondrial respiration in resistant cells. RNAi-mediated STAT3 silencing accelerated the sensitization of leukemia cells to nilotinib treatment, and STAT3-dependent energy metabolism regulation could be another underlying mechanism for regaining nilotinib response. CONCLUSION: Targeting STAT3 is an efficient strategy for improving the development of novel CML therapeutics for regaining nilotinib response, and re-sensitization of resistant cells could be mediated by induced apoptosis and regulation in energy metabolism. |
format | Online Article Text |
id | pubmed-9392574 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Mashhad University of Medical Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-93925742022-08-26 Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells Tezcanli Kaymaz, Burcin Selvi Gunel, Nur Sogutlu, Fatma Ozates Ay, Neslihan Pinar Baran, Yusuf Gunduz, Cumhur Biray Avci, Cigir Iran J Basic Med Sci Original Article OBJECTIVE(S): STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT3 activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing to resistance to TKI nilotinib. To investigate the possible therapeutic effects of targeting STAT3 to overcome nilotinib resistance by evaluating various cellular responses in both sensitive and nilotinib resistant CML cells and to test the hypothesis that energy metabolism modulation could be a mechanism for re-sensitization to nilotinib in resistant cells. MATERIALS AND METHODS: By using RNAi-mediated STAT3 gene silencing, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT mRNA transcripts, STAT3 total, pTyr705, pSer727 protein expression levels, and metabolic activity as energy metabolism was determined in CML model K562 cells, in vitro. RESULTS: Targeting STAT3 sensitized both parental and especially nilotinib resistant cells by decreasing leukemic cell survival; inducing leukemic cell apoptosis, and decreasing STAT3 mRNA and protein expression levels. Besides, cell energy phenotype was modulated by switching energy metabolism from aerobic glycolysis to mitochondrial respiration in resistant cells. RNAi-mediated STAT3 silencing accelerated the sensitization of leukemia cells to nilotinib treatment, and STAT3-dependent energy metabolism regulation could be another underlying mechanism for regaining nilotinib response. CONCLUSION: Targeting STAT3 is an efficient strategy for improving the development of novel CML therapeutics for regaining nilotinib response, and re-sensitization of resistant cells could be mediated by induced apoptosis and regulation in energy metabolism. Mashhad University of Medical Sciences 2022-07 /pmc/articles/PMC9392574/ /pubmed/36033954 http://dx.doi.org/10.22038/IJBMS.2022.64138.14121 Text en https://creativecommons.org/licenses/by/3.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/ (https://creativecommons.org/licenses/by/3.0/) ) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Tezcanli Kaymaz, Burcin Selvi Gunel, Nur Sogutlu, Fatma Ozates Ay, Neslihan Pinar Baran, Yusuf Gunduz, Cumhur Biray Avci, Cigir Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
title | Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
title_full | Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
title_fullStr | Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
title_full_unstemmed | Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
title_short | Investigating the potential therapeutic role of targeting STAT3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
title_sort | investigating the potential therapeutic role of targeting stat3 for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9392574/ https://www.ncbi.nlm.nih.gov/pubmed/36033954 http://dx.doi.org/10.22038/IJBMS.2022.64138.14121 |
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