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PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK

2016; Impact Journals LLC; Volume: 7; Issue: 50 Linguagem: Inglês

10.18632/oncotarget.12940

1949-2553

Tao Lu, Yanmei Zou, Guogang Xu, J.A. Potter, G.L. Taylor, Qiuhong Duan, Qin Yang, Huihua Xiong, Hong Qiu, Dawei Ye, Peng Zhang, Shiying Yu, Xianglin Yuan, Feng Zhu, Yihua Wang, Hua Xiong,

Phagocytosis and Immune Regulation

// Tao Lu 2, * , Yanmei Zou 1, * , Guogang Xu 3 , Jane A. Potter 4 , Garry L. Taylor 4 , Qiuhong Duan 2 , Qin Yang 5 , Huihua Xiong 1 , Hong Qiu 1 , Dawei Ye 1 , Peng Zhang 1 , Shiying Yu 1 , Xianglin Yuan 1 , Feng Zhu 2 , Yihua Wang 6 , Hua Xiong 1 1 Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China 2 Department of Biochemistry and molecular biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China 3 Nanlou Respiratory Department, Chinese PLA General Hospital, Beijing, 10083, China 4 BioMedical Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK 5 Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China 6 Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK * These authors have contributed equally to this work Correspondence to: Hua Xiong, email: cnhxiong@163.com Keywords: PRIMA-1 Met , MEK, p53, colorectal cancer, tumorigenesis Received: October 17, 2015 Accepted: October 10, 2016 Published: October 27, 2016 ABSTRACT PRIMA-1 Met is the methylated PRIMA-1 (p53 reactivation and induction of massive apoptosis) and could restore tumor suppressor function of mutant p53 and induce p53 dependent apoptosis in cancer cells harboring mutant p53. However, p53 independent activity of PRIMA-1 Met remains elusive. Here we reported that PRIMA-1 Met attenuated colorectal cancer cell growth irrespective of p53 status. Kinase profiling revealed that mitogen-activated or extracellular signal-related protein kinase (MEK) might be a potential target of PRIMA-1 Met . Pull-down binding and ATP competitive assay showed that PRIMA-1 Met directly bound MEK in vitro and in cells. Furthermore, the direct binding sites of PRIMA-1 Met were explored by using a computational docking model. Treatment of colorectal cancer cells with PRIMA-1 Met inhibited p53-independent phosphorylation of MEK, which in turn impaired anchorage-independent cell growth in vitro. Moreover, PRIMA-1 Met suppressed colorectal cancer growth in xenograft mouse model by inhibiting MEK1 activity. Taken together, our findings demonstrate a novel p53-independent activity of PRIMA-1 Met to inhibit MEK and suppress colorectal cancer growth.