PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK
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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.
Lu , T , Zou , Y , Xu , G , Potter , J A , Taylor , G L , Duan , Q , Yang , Q , Xiong , H , Qiu , H , Ye , D , Zhang , P , Yu , S , Yuan , X , Zhu , F , Wang , Y & Xiong , H 2016 , ' PRIMA-1 Met suppresses colorectal cancer independent of p53 by targeting MEK ' Oncotarget , vol 7 , no. 50 , pp. 83017-83030 . DOI: 10.18632/oncotarget.12940
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This work was supported by Grant No. 81201779 (Hua Xiong) from the National Natural Science Youth Foundation; Grant No. 81502118 (Yanmei Zou) from the National Natural Science Youth Foundation; Grant No. 2014CFB250 (Yanmei Zou) from the Natural Science Foundation of Hubei Province; Grant No. 81372434 (Huihua Xiong) from the National Natural Science Foundation.
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