H-Ras oncogene counteracts the growth-inhibitory effect of genistein in T24 bladder carcinoma cells.
Among eight human bladder cancer cell lines we examined, only T24 cells were resistant to the growth inhibition effect of genistein, an isoflavone and potent anticancer drug. Since the T24 cell line was the only cell line known to overexpress oncogenic H-Ras(val 12), we investigated the role of H-Ras(val 12) in mediating drug resistance. Herein, we demonstrate that the phenotype of T24 cells could be dramatically reversed and became relatively susceptible to growth inhibition by genistein if the synthesis of H-Ras(val 12) or its downstream effector c-Fos had been suppressed. The inhibition of Ras-mediated signalling with protein kinase inhibitors, such as PD58059 and U0126 which inhibited MEK and ERK, in T24 cells also rendered the identical phenotypic reversion. However, this reversion was not observed when an inhibitor was used to suppress the protein phosphorylation function of PI3 K or PKC. These results suggest that the signal mediated by H-Ras(val 12) is predominantly responsible for the resistance of the cells to the anticancer drug genistein.
Li
C
C
Department of Microbiology and Immunology, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Rd., Taichung 402, Taiwan, ROC.
Teng
R-H
RH
Tsai
Y-C
YC
Ke
H-S
HS
Huang
J-Y
JY
Chen
C-C
CC
Kao
Y-L
YL
Kuo
C-C
CC
Bell
W R
WR
Shieh
B
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D011905:Genes, ras; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D019833:Genistein; D011494:Protein Kinases