Contribution of the Src family of kinases to the appearance of malignant phenotypes in renal cancer cells.
Although the constitute activation of the Src family of kinases (Src) has been established as a poor prognostic factor in several types of cancer, the role of Src in renal cell carcinoma (RCC) has not been defined. This study aimed to determine whether Src could contribute to the appearance of malignant phenotypes in RCC. The role of Src in the appearance of malignant phenotypes in RCC was examined in two human renal cancer cell lines, Caki-1 from human metastatic RCC and ACHN from human primary RCC. Src activity in Caki-1 cells was higher than that in ACHN cells, and this difference corresponded to the difference of PP1 (a Src family inhibitor)-induced cytotoxicity on the two cells. The difference in cytotoxicity between the cells did not depend on cell cycle regulation but on the induction of apoptosis, and the difference in apoptosis particularly related to the reduction of the Bcl-xL level. Furthermore, in Caki-1 cells with higher Src activity, Src stimulated the production of vascular endothelial growth factor (VEGF), partially via the activation of Stat3, and the inhibition of Src activity caused a reduction of the VEGF level in serum, angiogenesis, and tumor development in a xenograft model. These results suggested that Src contributed to the appearance of malignant phenotypes in renal cancer cells, particularly due to the resistance against apoptosis by Bcl-xL and angiogenesis stimulated by Src-Stat3-VEGF signaling.
Yonezawa
Yuko
Y
Department of Food Science Research for Health, National Institute of Health and Nutrition, Tokyo, Japan.
Nagashima
Yoji
Y
Sato
Hiromi
H
Virgona
Nantiga
N
Fukumoto
Keiko
K
Shirai
Sumiko
S
Hagiwara
Hiromi
H
Seki
Taiichiro
T
Ariga
Toyohiko
T
Senba
Hironobu
H
Suzuki
Kazuyuki
K
Asano
Ryuji
R
Hagiwara
Kiyokazu
K
Yano
Tomohiro
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010641:Phenotype; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000145:classification* / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D011720:Pyrazoles; D011743:Pyrimidines; D016392:Proto-Oncogene Proteins pp60(c-src)