1. ¹Department of Microbiology and Immunology, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Rd., Taichung 402, Taiwan, ROC
2. ²Department of Biochemistry, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Rd., Taichung 402, Taiwan, ROC
3. ³Institute of Biomedical Sciences, National Chung Hsing University, No. 250, Kuo Kwang Rd., Taichung 402, Taiwan, ROC
4. ⁴Institute of Molecular Medicine, National Cheng Kung University Medical College, No. 1, Ta Hsueh Rd., Tainan 601, Taiwan, ROC
5. ⁵Department of Urology, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Rd., Taichung 402, Taiwan, ROC
6. ⁶Internal Medicine, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Rd., Taichung 402, Taiwan, ROC

Correspondence: Dr B Shieh, E-mail: chingli@csmu.edu.tw

Received 5 May 2004; Revised 27 October 2004; Accepted 29 October 2004; Published online 21 December 2004.

Abstract

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.