Requirement for epithelial p38α in KRAS-driven lung tumor progression

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.

Diversity and versatility of p38 kinase signalling in health and disease

“…However, there is also evidence from diverse experimental systems showing that this pathway is often harnessed by malignant cells to support tumour progression 214 . Thus, studies in mouse models of colon, breast and lung cancer indicate that p38α can engage different mechanisms in cancer cells to support primary tumour growth in vivo, including the modulation of intracellular signalling pathways that control cell survival and proliferation, the regulation of DNA repair or the production of extracellular factors that support cancer cell proliferation 117 , 213 , 215 , 216 . Moreover, p38α may promote metastasis of breast cancer, ovarian cancer and melanoma cells by targeting various proteins involved in the regulation of epithelial–mesenchymal transition, cell migration and extravasation 217 – 221 .…”

CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

“…In line, epithelial p38 was assigned a crucial role in the progression of KRAS G12V -driven lung cancer and p38 has been implicated in transformation and proliferation of lung cancer cells in in vivo models. High levels of p38 correlate with poor survival in lung adenocarcinoma patients [150]. Of note, studies combining p38 inhibition in conjunction with chemotherapeutic agents such as cisplatin, irinotecan or arsenic trioxide showed opposing results and led to the acceleration of tumor growth upon p38 inhibition [53][54][55]57,[151][152][153].…”

Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells

“…In addition, several intracellular signaling factors including Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) are activated in the microenvironment [ 25 ]. The expression levels of phosphorylated (p)-p38 and p-JNK in human non-small cell lung cancer (NSCLC) tissues are higher than those in normal tissues [ 26 ]. The improvement of stress conditions or inhibition of stress response signals may be useful to prevent the tumor progression.…”