title: PAK1 confers chemoresistance and poor outcome in non-small cell lung cancer via β-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 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.
authors.affiliation: Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Ming-Jenn
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yao-Chen
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Surgery, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chi-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D051176:beta Catenin / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C495270:CTNNB1 protein, human; D051176:beta Catenin; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D002945:Cisplatin