Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein.
BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1-targeted cancer treatment in animals.
Yang
Qingkai
Q
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Deng
Xianming
X
Lu
Bingwen
B
Cameron
Michael
M
Fearns
Colleen
C
Patricelli
Matthew P
MP
Yates
John R
JR
Gray
Nathanael S
NS
Lee
Jiing-Dwan
JD
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D048054:Mitogen-Activated Protein Kinase 7