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

被引:28
作者
Chen, Ming-Jenn [1 ]
Wu, De-Wei [2 ]
Wang, Yao-Chen [3 ]
Chen, Chi-Yi [4 ]
Lee, Huei [2 ]
机构
[1] Chi Mei Med Ctr, Dept Surg, Tainan, Taiwan
[2] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Taipei, Taiwan
[3] Chung Shan Med Univ, Dept Internal Med, Taichung, Taiwan
[4] Chung Shan Med Univ, Dept Surg, Taichung, Taiwan
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; DRUG-RESISTANCE; P21-ACTIVATED-KINASE-1; ACTIVATION; INDUCE; PHOSPHORYLATION; APOPTOSIS;
D O I
10.1038/srep34933
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-catenin expression through ERK/GSK3 beta signaling. The increased beta-catenin expression promotes sphere cell formation and expression of stemness markers and this beta-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 beta-catenin expression in lung tumors. Patients with high-PAK1, high-pERK, and high-nuclear beta-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 beta-catenin tumors. In conclusion, PAK1 confers cisplatin resistance in NSCLC via beta-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.
引用
收藏
页数:9
相关论文
共 29 条
[1]   Opinion - Migrating cancer stem cells - an integrated concept of malignant tumour progression [J].
Brabletz, T ;
Jung, A ;
Spaderna, S ;
Hlubek, F ;
Kirchner, T .
NATURE REVIEWS CANCER, 2005, 5 (09) :744-749
[2]   PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway [J].
Coles, LC ;
Shaw, PE .
ONCOGENE, 2002, 21 (14) :2236-2244
[3]   Role of Wnt/β-catenin Signaling in Drug Resistance of Pancreatic Cancer [J].
Cui, Jiujie ;
Jiang, Weihua ;
Wang, Shuyi ;
Wang, Liwei ;
Xie, Keping .
CURRENT PHARMACEUTICAL DESIGN, 2012, 18 (17) :2464-2471
[4]   Wnt/β-catenin signaling in cancer stemness and malignant behavior [J].
Fodde, Riccardo ;
Brabletz, Thomas .
CURRENT OPINION IN CELL BIOLOGY, 2007, 19 (02) :150-158
[5]   α6β4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-κB-dependent resistance to apoptosis in 3D mammary acini [J].
Friedland, Julie C. ;
Lakins, Johnathon N. ;
Kazanietz, Marcelo G. ;
Chernoff, Jonathan ;
Boettiger, David ;
Weaver, Valerie M. .
JOURNAL OF CELL SCIENCE, 2007, 120 (20) :3700-3712
[6]  
Gandevia B., 1964, Med J Aust., V2, P320, DOI [10.5694/j.1326-5377.1964.tb115781.x, DOI 10.5694/J.1326-5377.1964.TB115781.X]
[7]   Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer [J].
Hermann, Patrick C. ;
Huber, Stephan L. ;
Herrler, Tanja ;
Aicher, Alexandra ;
Ellwart, Joachim W. ;
Guba, Markus ;
Bruns, Christiane J. ;
Heeschen, Christopher .
CELL STEM CELL, 2007, 1 (03) :313-323
[8]   Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients [J].
Holm, Caroline ;
Rayala, Suresh ;
Jirstrom, Karin ;
Stal, Olle ;
Kumar, Rakesh ;
Landberg, Goeran .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (10) :671-680
[9]   P21-activated kinase 1 stimulates colon cancer cell growth and migration/invasion via ERK- and AKT-dependent pathways [J].
Huynh, Nhi ;
Liu, Kevin H. ;
Baldwin, Graham S. ;
He, Hong .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2010, 1803 (09) :1106-1113
[10]   Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype [J].
Jang, Gyu-Beom ;
Kim, Ji-Young ;
Cho, Sung-Dae ;
Park, Ki-Soo ;
Jung, Ji-Youn ;
Lee, Hwa-Yong ;
Hong, In-Sun ;
Nam, Jeong-Seok .
SCIENTIFIC REPORTS, 2015, 5