PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via ?-catenin-mediated stemness.

ABSTRACT: PAK1 confers resistance to the estrogen antagonist tamoxifen in breast cancer. However, a role for PAK1 remains to be elucidated for chemoresistance and prognosis in non-small cell lung cancer (NSCLC). We provide evidence that PAK1 confers cisplatin resistance by increasing ?-catenin expression through ERK/GSK3? signaling. The increased ?-catenin expression promotes sphere cell formation and expression of stemness markers and this ?-catenin-induced stemness is responsible for PAK1-mediated cisplatin resistance. We enrolled 87 NSCLC patients who had received cisplatin-based chemotherapy to confirm the association between PAK1 expression and response to chemotherapy and outcomes. PAK1 expression, evaluated by immunohistochemistry, was positively correlated with pERK and ?-catenin expression in lung tumors. Patients with high-PAK1, high-pERK, and high-nuclear ?-catenin tumors more frequently showed an unfavorable response to cisplatin-based chemotherapy when compared to their counterparts. Kaplan-Meier and Cox regression analysis also indicated a poorer overall survival (OS) and relapse free survival (RFS) in patients with high-PAK1, high-pERK, and high-nuclear ?-catenin tumors. In conclusion, PAK1 confers cisplatin resistance in NSCLC via ?-catenin-mediated stemness. Therefore, we suggest that clinical use of a combination of the MEK/ERK inhibitor AZD6244 and cisplatin might improve sensitivity to cisplatin-based chemotherapy and outcomes in NSCLC patients who harbor high-PAK1-expressing tumors.

SUBMITTER: Chen MJ 

PROVIDER: S-EPMC5054675 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature