A Src family inhibitor (PP1) potentiates tumor-suppressive effect of connexin 32 gene in renal cancer cells.
Connexin (Cx) genes exert negative growth effects on tumor cells with certain cell specificity. We have recently reported that Cx32 acts as a tumor suppressor gene in renal cancer cells due to the inhibition of Src-dependent signaling. In line with the previous study, here we examined if a Src family inhibitor (PP1) could potentiate tumor-suppressive effect of Cx32 in Caki-2 cell from human renal cell carcinoma. In order to clarify the potentialization of PP1, using Cx32-transfected Caki-2 cells and mock-transfected Caki-2 cells, we estimated difference in cytotoxic effect of PP1 on the two cell clones in vitro as well as in vivo. PP1 showed more cytotoxic effect on Caki-2 cells having Cx32 positive expression than that of Cx32 negative expression at lower doses. This potentialization was also observed in xenograft model of nude mice. The potentialization of the effect mainly depended on the induction of apoptosis but not the control of cell growth. In conjugation with this event, the reduction of anti-apoptotic molecules (Bcl-2 and Bcl-xL) was caused by the combination of Cx32 expression and PP1 treatment in Caki-2 cells. These results suggest that PP1 potentiates tumor-suppressive effect of connexin 32 gene in renal cancer cells through the reduction of anti-apoptotic molecules.
Fujimoto
Eriko
E
Department of Food Science Research for Health, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan; Faculty of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
Sato
Hiromi
H
Nagashima
Yoji
Y
Negishi
Etsuko
E
Shirai
Sumiko
S
Fukumoto
Keiko
K
Hagiwara
Hiromi
H
Hagiwara
Kiyokazu
K
Ueno
Koichi
K
Yano
Tomohiro
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011743:Pyrimidines; D051020:bcl-X Protein; D019061:src-Family Kinases; D000097002:Gap Junction beta-1 Protein; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse