Official websites use. Share sensitive information only on official, secure websites. E-mail: chingli csmu. This article is licensed under a Creative Commons Attribution 4. 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. 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.
Keywords: H-Ras, bladder transitional cell carcinoma, genistein, microarray profiling gene expression pattern, drug resistance. Ras transduces signals in discrete intracellular pathways Marshall, , with the route via raf-1, MEK, ERK, and finally to induce the expression of the immediate early gene c -fos for turning on a cascade of downstream genes as the most prominent pathway in regulating vital cellular processes Rayter et al , ; Thorburn and Thorburn, ; Maculuso et al , Mutational activation transforms Ras into an oncogenic form, as demonstrated by the substitution of glycine by valine at codon 12 in Harvey H -Ras H-Ras val 12 , results in the loss of intrinsic GTPase function and therefore the protein is constitutively in the active, GTP-bound state and is continuously sending signals for cell growth Rayter et al , ; Maculuso et al , According to the recent surveys of the WHO www.
Transitional cell carcinoma TCC is a tumour that occurs mostly in the urinary bladder and has been linked to multiple and accumulated aberrations in oncogenes e. H-ras mutations and cancer-suppressor genes e. Mutational activation of the H-ras oncogene was first reported Reddy et al , ; Tabin et al , in human T24 TCC cell line that played an essential role in urothelial carcinogenesis.
Therefore, oncogenic activation of H-Ras is an important tumorigenic factor for bladder tumours. High soybean food consumption, which provides ingestion of a substantial amount of genistein, has been suggested to contribute to the relatively low rates of many cancers in Asian countries Lee et al , ; Messina et al , Genistein, an isoflavone with a structure similar to oestrogen a phyto-oestrogen , possesses potent inhibitory activities against growth factor-associated tyrosine protein kinases Akiyama et al , and DNA topoisomerase II Markovits et al , It is also an antioxidant Naim et al , with the capability of suppressing angiogenesis and endothelial cell proliferation in vitro Fotsis et al , Genistein is a compound with a variety of potential properties that mainly inhibit tumour growth in vitro and in vivo.
