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Overexpression of the csk gene suppresses tumor metastasis in vivo
Author(s) -
Nakagawa Takumi,
Tanaka Sakae,
Suzuki Hiroyuki,
Takayanagi Hiroshi,
Miyazaki Tsuyoshi,
Nakamura Kozo,
Tsuruo Takashi
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20001101)88:3<384::aid-ijc10>3.0.co;2-b
Subject(s) - proto oncogene tyrosine protein kinase src , tyrosine protein kinase csk , cancer research , biology , tyrosine kinase , metastasis , src family kinase , microbiology and biotechnology , receptor tyrosine kinase , kinase , cancer , signal transduction , sh2 domain , genetics
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. Int. J. Cancer 88:384–391, 2000. © 2000 Wiley‐Liss, Inc.