Requirement for PKC epsilon in KRAS-driven lung tumorigenesis

Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study,...

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Autores principales: Garg, Rachana, Cooke, Mariana, Wang, Shaofei, Benavides, Fernando, Abba, Martín Carlos, Cicchini, Michelle, Feldser, David M., Kazanietz, Marcelo G.
Formato: Articulo Preprint
Lenguaje:Español
Publicado: 2020
Materias:
Ciencias Médicas
PKCe
KRas
carcinogens
mice
lung cancer
adenocarcinoma
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/126740
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-126740
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Español
topic Ciencias Médicas
PKCe
KRas
carcinogens
mice
lung cancer
adenocarcinoma
spellingShingle Ciencias Médicas
PKCe
KRas
carcinogens
mice
lung cancer
adenocarcinoma
Garg, Rachana
Cooke, Mariana
Wang, Shaofei
Benavides, Fernando
Abba, Martín Carlos
Cicchini, Michelle
Feldser, David M.
Kazanietz, Marcelo G.
Requirement for PKC epsilon in KRAS-driven lung tumorigenesis
topic_facet Ciencias Médicas
PKCe
KRas
carcinogens
mice
lung cancer
adenocarcinoma
description Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCepsilon, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCepsilon expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCepsilon-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCepsilon-/- mice) we were able to demonstrate the requirement of PKCepsilon for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCepsilon-deficient KRAS-dependent NSCLC cells. Moreover, PKCepsilon-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCepsilon and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCepsilon in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCepsilon for lung cancer therapeutics.
format Articulo
Preprint
author Garg, Rachana
Cooke, Mariana
Wang, Shaofei
Benavides, Fernando
Abba, Martín Carlos
Cicchini, Michelle
Feldser, David M.
Kazanietz, Marcelo G.
author_facet Garg, Rachana
Cooke, Mariana
Wang, Shaofei
Benavides, Fernando
Abba, Martín Carlos
Cicchini, Michelle
Feldser, David M.
Kazanietz, Marcelo G.
author_sort Garg, Rachana
title Requirement for PKC epsilon in KRAS-driven lung tumorigenesis
title_short Requirement for PKC epsilon in KRAS-driven lung tumorigenesis
title_full Requirement for PKC epsilon in KRAS-driven lung tumorigenesis
title_fullStr Requirement for PKC epsilon in KRAS-driven lung tumorigenesis
title_full_unstemmed Requirement for PKC epsilon in KRAS-driven lung tumorigenesis
title_sort requirement for pkc epsilon in kras-driven lung tumorigenesis
publishDate 2020
url http://sedici.unlp.edu.ar/handle/10915/126740
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bdutipo_str Repositorios
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