PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy
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Jian Chen1,*, Huijun Lu2,*, Dongwang Yan1, Feifei Cui1, Xiaoliang Wang1, Fudong Yu1, Yingming Xue1, Xiaodong Feng3, Jingtao Wang1, Xiao Wang1, Tao Jiang4, Meng Zhang2, Senlin Zhao1, Yang Yu1, Huamei Tang2 and Zhihai Peng1
1 Department of General Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
2 Department of Pathology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
3 Basic Medical College, Taishan Medical University, Tai’an, People’s Republic of China
4 Department of Anal-Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, People‘s Republic of China
* These authors contributed equally to this work
Zhihai Peng, email:
Huamei Tang, email:
Keywords: p21-activated kinase 6, Colon cancer, 5-fluorouracil, Chemoresistance
Received: June 09, 2014 Accepted: November 07, 2014 Published: November 07, 2014
p21-Activated kinase 6 (PAK6) has been implicated in radiotherapy and docetaxel resistance. We have further evaluated PAK6 as a predictor of 5-fluorouracil (5-FU) treatment response in colon cancer. Here we report that in colon cancer PAK6 promotes tumor progression and chemoresistance both in vitro and in vivo. In the clinical analysis, PAK6 was overexpressed in 104 of 147 (70.75%) stage II and III patients who received 5-FU based chemotherapy after surgery. Multivariate Cox regression analysis indicated that PAK6 was an independent prognostic factor for overall survival (P < 0.001) and disease-free survival (P < 0.001). Colon cancer cell lines showed increased PAK6 expression upon 5-FU treatment. In PAK6-knockdown cells treated with 5-FU, cell viability and phosphorylation of BAD decreased, and the number of apoptotic cells, levels of cleaved caspase 3 and PARP increased compared to control cells. The opposite was observed in PAK6 overexpressing cells. Short hairpin RNA knockdown of PAK6 blocked cells in G2-M phase. Furthermore, Animal experiments results in vivo are consistent with outcomes in vitro. This study demonstrates that PAK6 is an independent prognostic factor for adjuvant 5-FU-based chemotherapy in patients with stage II and stage III colon cancer.
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