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

Ming Jenn Chen, De Wei Wu, Yao Chen Wang, Chi Yi Chen, Huei Lee

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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 β-catenin expression through ERK/GSK3β signaling. The increased β-catenin expression promotes sphere cell formation and expression of stemness markers and this β-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 β-catenin expression in lung tumors. Patients with high-PAK1, high-pERK, and high-nuclear β-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 β-catenin tumors. In conclusion, PAK1 confers cisplatin resistance in NSCLC via β-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.

Original languageEnglish
Article number34933
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Oct 7 2016

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Catenins
Non-Small Cell Lung Carcinoma
Cisplatin
Drug Therapy
Neoplasms
Estrogen Antagonists
Survival
Mitogen-Activated Protein Kinase Kinases
Tamoxifen
Immunohistochemistry
Regression Analysis
Breast Neoplasms
Recurrence
Lung

ASJC Scopus subject areas

  • General

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PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via β-catenin-mediated stemness. / Chen, Ming Jenn; Wu, De Wei; Wang, Yao Chen; Chen, Chi Yi; Lee, Huei.

In: Scientific Reports, Vol. 6, 34933, 07.10.2016.

Research output: Contribution to journalArticle

Chen, Ming Jenn ; Wu, De Wei ; Wang, Yao Chen ; Chen, Chi Yi ; Lee, Huei. / PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via β-catenin-mediated stemness. In: Scientific Reports. 2016 ; Vol. 6.
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