Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A.
Methionine S-adenosyltransferase 2A (MAT2A) is the catalytic subunit for synthesis of S-adenosylmethionine (SAM), the principal methyl donor in many biological processes. MAT2A is up-regulated in many cancers, including liver cancer and colorectal cancer (CRC) and is a potentially important drug target. We developed a family of fluorinated N,N-dialkylaminostilbene agents, called FIDAS agents, that inhibit the proliferation of CRC cells in vitro and in vivo. Using a biotinylated FIDAS analogue, we identified the catalytic subunit of MAT2A as the direct and exclusive binding target of these FIDAS agents. MAT2B, an associated regulatory subunit of MAT2A, binds indirectly to FIDAS agents through its association with MAT2A. FIDAS agents inhibited MAT2A activity in SAM synthesis, and depletion of MAT2A by shRNAs inhibited CRC cell growth. A novel FIDAS agent delivered orally repressed CRC xenografts in athymic nude mice. These findings suggest that FIDAS analogues targeting MAT2A represent a family of novel and potentially useful agents for cancer treatment.
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40506-0509, USA.
Wen
W
Zhang
Vitaliy
V
Sviripa
Xi
X
Chen
Jiandang
J
Shi
Tianxin
T
Yu
Adel
A
Hamza
Nicholas D
ND
Ward
Liliia M
LM
Kril
Craig W
CW
Vander Kooi
Chang-Guo
CG
Zhan
B Mark
BM
Evers
David S
DS
Watt
Chunming
C
Liu
D000818:Animals; D055162:Biocatalysis; D003110:Colonic Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D013267:Stilbenes; D005461:Fluorine; D008716:Methionine Adenosyltransferase