Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:83017-83030. https://doi.org/10.18632/oncotarget.12940

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Abstract

Tao Lu2,*, Yanmei Zou1,*, Guogang Xu3, Jane A. Potter4, Garry L. Taylor4, Qiuhong Duan2, Qin Yang5, Huihua Xiong1, Hong Qiu1, Dawei Ye1, Peng Zhang1, Shiying Yu1, Xianglin Yuan1, Feng Zhu2, Yihua Wang6, Hua Xiong1

1Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China

2Department of Biochemistry and molecular biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China

3Nanlou Respiratory Department, Chinese PLA General Hospital, Beijing, 10083, China

4BioMedical Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK

5Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China

6Biological 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-1Met, MEK, p53, colorectal cancer, tumorigenesis

Received: October 17, 2015    Accepted: October 10, 2016    Published: October 27, 2016

ABSTRACT

PRIMA-1Met 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-1Met remains elusive. Here we reported that PRIMA-1Met 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-1Met. Pull-down binding and ATP competitive assay showed that PRIMA-1Met directly bound MEK in vitro and in cells. Furthermore, the direct binding sites of PRIMA-1Met were explored by using a computational docking model. Treatment of colorectal cancer cells with PRIMA-1Met inhibited p53-independent phosphorylation of MEK, which in turn impaired anchorage-independent cell growth in vitro. Moreover, PRIMA-1Met suppressed colorectal cancer growth in xenograft mouse model by inhibiting MEK1 activity.

Taken together, our findings demonstrate a novel p53-independent activity of PRIMA-1Met to inhibit MEK and suppress colorectal cancer growth.


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