Expression of Src and FAK in hepatocellular carcinoma and the effect of Src inhibitors on hepatocellular carcinoma in vitro.
The expressions of c-Src and focal adhesion kinase (FAK) were studied in 65 Chinese patients with hepatocellular carcinoma (HCC) by immunohistochemistry using rabbit monoclonal antibodies. Expressions of total Src, an active form of Src, and FAK were found in 44/65 (67.7%), 36/45 (55.4%), and 33/56 (58.9%) HCC cases, respectively. There was a good correlation between the expression of total Src, active form of Src, and FAK in these HCC cases (P < 0.001). Expression of Src was not correlated to any clinical parameters, cancer cell phenotypic markers, and pathologic features apart from a positive correlation with alpha-fetoprotein (P < 0.01). The expression of FAK was correlated with earlier onset and the expression of Ki-67 but not proliferating cell nuclear antigen (PCNA) in these HCC cases. Four liver-cancer-derived cell lines (three derived from HCC and one from hepatoblastoma) were then tested with inhibitors against Src. A small molecule, KX2-391, designed to target the substrate binding pocket of Src, was found to have more broad-spectrum activity and better potency than Dasatinib, an adenosine triphosphate (ATP)-competitive inhibitor in vitro. Our data indicates that Src and FAK expression are both elevated and active in Chinese patients with HCC and that Src may play a key role in supporting HCC progression. Src antagonism with specific inhibitors may be an attractive treatment paradigm for patients with HCC.
Lau
Grace M
GM
Kinex Pharmaceuticals, New York State Center of Excellence in Bioinformatics and Life Sciences, 701 Elliott Street, Buffalo, NY 14203, USA.
Lau
Gillian M
GM
Yu
Guo-Liang
GL
Gelman
Irwin H
IH
Gutowski
Alan
A
Hangauer
David
D
Fang
Jane W S
JW
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D000069439:Dasatinib; D018450:Disease Progression; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D013844:Thiazoles; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib