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Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of person...

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Autores principales: Stulpinas, Aurimas, Sereika, Matas, Vitkeviciene, Aida, Imbrasaite, Ausra, Krestnikova, Natalija, Kalvelyte, Audrone V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9848735/
https://www.ncbi.nlm.nih.gov/pubmed/36686779
http://dx.doi.org/10.3389/fonc.2022.1045521
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author Stulpinas, Aurimas
Sereika, Matas
Vitkeviciene, Aida
Imbrasaite, Ausra
Krestnikova, Natalija
Kalvelyte, Audrone V.
author_facet Stulpinas, Aurimas
Sereika, Matas
Vitkeviciene, Aida
Imbrasaite, Ausra
Krestnikova, Natalija
Kalvelyte, Audrone V.
author_sort Stulpinas, Aurimas
collection PubMed
description There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients’ lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling – selumetinib, trametinib, and SCH772984 – increased AKT phosphorylation, and conversely, inhibitors of AKT – capivasertib, idelalisib, and AKT inhibitor VIII – increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy.
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spelling pubmed-98487352023-01-19 Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models Stulpinas, Aurimas Sereika, Matas Vitkeviciene, Aida Imbrasaite, Ausra Krestnikova, Natalija Kalvelyte, Audrone V. Front Oncol Oncology There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients’ lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling – selumetinib, trametinib, and SCH772984 – increased AKT phosphorylation, and conversely, inhibitors of AKT – capivasertib, idelalisib, and AKT inhibitor VIII – increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy. Frontiers Media S.A. 2023-01-04 /pmc/articles/PMC9848735/ /pubmed/36686779 http://dx.doi.org/10.3389/fonc.2022.1045521 Text en Copyright © 2023 Stulpinas, Sereika, Vitkeviciene, Imbrasaite, Krestnikova and Kalvelyte 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
Stulpinas, Aurimas
Sereika, Matas
Vitkeviciene, Aida
Imbrasaite, Ausra
Krestnikova, Natalija
Kalvelyte, Audrone V.
Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models
title Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models
title_full Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models
title_fullStr Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models
title_full_unstemmed Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models
title_short Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models
title_sort crosstalk between protein kinases akt and erk1/2 in human lung tumor-derived cell models
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9848735/
https://www.ncbi.nlm.nih.gov/pubmed/36686779
http://dx.doi.org/10.3389/fonc.2022.1045521
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