P38α suppresses tumor iniating cell phenotypes through inhibition of NFATc4 in non-small cell lung cancer

Abstract

The p38 MAPK pathway can be activated by stress stimuli and inflammatory cytokines, and involved in a wide range of cellular process in context-specific manner. P38α, a member of the p38 family, is known to have both tumor suppressive role and tumor supportive role in different cancers. It is reported that p38 regulates self-renewal and differentiation in lung stem cell, and inactivation of p38α in the lung epithelium leads to K-RasG12V induced tumorigenesis. However, whether p38α is involved in regulating tumor initiating cells (TICs) remains unclear. By immunohistochemistry, nuclear expression of activated p38 (p-p38) were analysed in 90 lung adenocarcinomas. Our results showed that high p-p38 expression was significantly correlated with better patient outcome, and also correlated with well differentiated carcinomas compared with poor differentiated carcinomas. This data indicates that p38 might play a tumor suppressive role and drive tumor differentiation in lung cancer. Here, we further addressed the functional role of p38 in lung TIC regulation. Suppression of p38 lead to increase in ALDH+/CD44+-TIC population. Both knockdown of p38α by siRNA or p38α inhibition by SB203580 up-regulated the expressions of pluripotency genes (SOX2, OCT4, NANOG). Functionally, p38 inhibition by SB203580 could promote the growth of tumor spheres for two consecutive generations. The mechanisms of the suppressive effect of p38α on lung TIC was further investigated. The transcription factor NFATc4 is a member of the Nuclear Factors of Activated T-cells (NFATs) family that can be activated by dephosphorylation and nuclear translocation. By western blot, we found that inhibition of p38α increased the expression of nuclear NFATc4. Moreover, knockdown of NFATc4 lead to suppression of sphere formation and pluripotency gene expression in lung cancer cell lines. Together, these results indicate that p38α supresses lung TIC function through inhibition of NFATc4 activity.