Requirement for epithelial p38α in KRAS-driven lung tumor progression
| Autor: | Alberto Villanueva, Angel R. Nebreda, Jessica Vitos-Faleato, Nuria Gutierrez-Prat, Sebastián M Real, Matthias Drosten, Elisabet Llonch, Mariano Barbacid |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Lung Neoplasms
Adenocarcinoma of Lung Epithelial cells Biology medicine.disease_cause Malignant transformation Mitogen-Activated Protein Kinase 14 Proto-Oncogene Proteins p21(ras) Ciencias Biológicas purl.org/becyt/ford/1 [https] Mice TIMP-1 Cell Line Tumor medicine KRAS Animals Humans Progenitor cell Lung cancer Autocrine signalling purl.org/becyt/ford/1.6 [https] Lung Cell Proliferation Neoplastic Processes Cèl·lules epitelials Multidisciplinary Biological Sciences Bioquímica y Biología Molecular medicine.disease Mice Inbred C57BL Disease Models Animal P38Α LUNG ADENOCARCINOMA Cancer cell Disease Progression Cancer research Càncer de pulmó Adenocarcinoma Signal transduction CIENCIAS NATURALES Y EXACTAS NONONCOGENE ADDICTION |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET Proc Natl Acad Sci U S A |
| Popis: | 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. Fil: Vitos Faleato, Jessica. Instituto de Investigación Biomédica de Barcelona.; España Fil: Real Varela, Sebastián Martín. Instituto de Investigación Biomédica de Barcelona.; España Fil: Gutiérrez Prat, Nuria. Instituto de Investigación Biomédica de Barcelona.; España Fil: Villanueva, Alberto. Instituto Catalán de Oncología; España Fil: Llonch llongueras, Elisabet. Instituto de Investigación Biomédica de Barcelona.; España Fil: Drosten, Matthias. Centro Nacional de Investigaciones Oncologicas; España Fil: Barbacid, Mariano. Centro Nacional de Investigaciones Oncologicas; España Fil: Nebreda, Ángel R.. Instituto de Investigación Biomédica de Barcelona.; España |
| Databáze: | OpenAIRE |
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