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Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2588-2596. doi: 10.1073/pnas.1921404117. Epub 2020 Jan 22.

Requirement for epithelial p38α in KRAS-driven lung tumor progression.

Author information

1
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
2
Program Against Cancer Therapeutic Resistance, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, 08907 L'Hospitalet de Llobregat, Spain.
3
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain.
4
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; angel.nebreda@irbbarcelona.org.
5
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.

Abstract

Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.

KEYWORDS:

KRAS; TIMP-1; lung adenocarcinoma; nononcogene addiction; p38α

PMID:
31969449
PMCID:
PMC7007552
[Available on 2020-07-22]
DOI:
10.1073/pnas.1921404117

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