Overexpression of the csk gene suppresses tumor metastasis in vivo.
The non-receptor tyrosine kinase c-Src has been implicated in the development of numerous human cancers. c-Src is activated in colon cancers, particularly in highly metastatic cells, and its overexpression strongly correlates with tumor progression. C-terminal Src kinase (Csk) has been demonstrated to negatively regulate Src family tyrosine kinases through tyrosine phosphorylation at the C-terminal regulatory site (Tyr-527). We report herein that down-regulation of Src kinase activity by adenovirus-mediated csk gene transfer abrogated the highly metastatic phenotype of colon cancer cells. Overexpression of Csk decreased Src tyrosine kinase activity in NL-17 cells, the highly metastatic clone of mouse colon adenocarcinoma 26. Importantly, Csk overexpression in NL-17 cells resulted in significant suppression of in vivo metastasis, without affecting its tumorgenicity. Csk overexpression decreased the invasiveness of NL-17 cells through Matrigel, in vitro reconstituted basement membrane. Gelatin zymography confirmed the decreased protein levels of MMP-2 (gelatinase A) in the supernatants of Csk-overexpressed NL- 17 cells. These results provide a therapeutic basis for interfering with metastasis of colon cancer by csk gene-mediated down-regulation of Src kinase activity.
Nakagawa
T
T
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Tanaka
S
S
Suzuki
H
H
Takayanagi
H
H
Miyazaki
T
T
Nakamura
K
K
Tsuruo
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D003110:Colonic Neoplasms / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020778:Matrix Metalloproteinase 2