Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling.
Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Δ716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Masahiro
M
Sonoshita
Masahiro
M
Aoki
Haruhiko
H
Fuwa
Koji
K
Aoki
Hisahiro
H
Hosogi
Yoshiharu
Y
Sakai
Hiroki
H
Hashida
Arimichi
A
Takabayashi
Makoto
M
Sasaki
Sylvie
S
Robine
Kazuyuki
K
Itoh
Kiyoko
K
Yoshioka
Fumihiko
F
Kakizaki
Takanori
T
Kitamura
Masanobu
M
Oshima
Makoto Mark
MM
Taketo
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D044483:Intestinal Polyposis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D015530:Nuclear Matrix / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology
C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; D056970:Co-Repressor Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008024:Ligands; C497762:Notch1 protein, mouse; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch; D012097:Repressor Proteins; C498445:TLE5 protein, human; C434946:Tle1 protein, mouse; C089462:Tle5 protein, mouse; D014157:Transcription Factors