Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/80207 |
Resumo: | KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations. |
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Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implicationsKRAS mutationscell death resistanceapoptosisautophagyCiências Médicas::Medicina ClínicaScience & TechnologyKRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations.This work was financed by the Portuguese Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia, FCT) through two PhD grants, SFRH/BD/142486/2018 and SFRH/BD/140137/2018, attributed to A.F. and F.P, respectively. A.P. acknowledges FCT within the scope of the project PTDC/QUIQIN/28662/2017. A.P. and M.J.S. also acknowledge the support of the CBMA strategic programme “Contrato-Programa” UIDB/04050/2020 funded by national funds through the FCT I.P. C.A.R. acknowledges the project Norte-01-0145-FEDER-000051—“Cancer Research on Therapy Resistance: From Basic Mechanisms to Novel Targets”, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). M.J.O. acknowledges FEDER funds through COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, Portuguese funds through FCT/Ministério da Ciência, Tecnologia e do Ensino Superior.MDPIUniversidade do MinhoFerreira, AnabelaPereira, FláviaReis, CelsoOliveira, Maria JoséSousa, Maria JoãoPreto, Ana2022-07-132022-07-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/80207engFerreira, A.; Pereira, F.; Reis, C.; Oliveira, M.J.; Sousa, M.J.; Preto, A. Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications. Cells 2022, 11, 2183. https://doi.org/10.3390/cells111421832073-440910.3390/cells1114218335883626https://www.mdpi.com/2073-4409/11/14/2183info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:38:57Zoai:repositorium.sdum.uminho.pt:1822/80207Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:35:30.176800Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
title |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
spellingShingle |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications Ferreira, Anabela KRAS mutations cell death resistance apoptosis autophagy Ciências Médicas::Medicina Clínica Science & Technology |
title_short |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
title_full |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
title_fullStr |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
title_full_unstemmed |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
title_sort |
Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications |
author |
Ferreira, Anabela |
author_facet |
Ferreira, Anabela Pereira, Flávia Reis, Celso Oliveira, Maria José Sousa, Maria João Preto, Ana |
author_role |
author |
author2 |
Pereira, Flávia Reis, Celso Oliveira, Maria José Sousa, Maria João Preto, Ana |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Ferreira, Anabela Pereira, Flávia Reis, Celso Oliveira, Maria José Sousa, Maria João Preto, Ana |
dc.subject.por.fl_str_mv |
KRAS mutations cell death resistance apoptosis autophagy Ciências Médicas::Medicina Clínica Science & Technology |
topic |
KRAS mutations cell death resistance apoptosis autophagy Ciências Médicas::Medicina Clínica Science & Technology |
description |
KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-07-13 2022-07-13T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/80207 |
url |
https://hdl.handle.net/1822/80207 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Ferreira, A.; Pereira, F.; Reis, C.; Oliveira, M.J.; Sousa, M.J.; Preto, A. Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications. Cells 2022, 11, 2183. https://doi.org/10.3390/cells11142183 2073-4409 10.3390/cells11142183 35883626 https://www.mdpi.com/2073-4409/11/14/2183 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799132880501211136 |