PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK.
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.
Department of Biochemistry and molecular biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China.
Tao
T
Lu
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Yanmei
Y
Zou
Nanlou Respiratory Department, Chinese PLA General Hospital, Beijing, 10083, China.
Guogang
G
Xu
BioMedical Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK.
Jane A
JA
Potter
BioMedical Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK.
Garry L
GL
Taylor
Department of Biochemistry and molecular biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China.
Qiuhong
Q
Duan
Department of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Qin
Q
Yang
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Huihua
H
Xiong
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hong
H
Qiu
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Dawei
D
Ye
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Peng
P
Zhang
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Shiying
S
Yu
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Xianglin
X
Yuan
Department of Biochemistry and molecular biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China.
Feng
F
Zhu
Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
Yihua
Y
Wang
Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hua
H
Xiong
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011812:Quinuclidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C533410:eprenetapopt
MEK; PRIMA-1Met; colorectal cancer; p53; tumorigenesis