Luteolin suppress bladder cancer growth via regulation of mechanistic target of rapamycin (mTOR) pathway

概要

Luteolin is a natural flavonoid with strong anti-oxidative properties that is reported to have an anti-cancer effect in several malignancies other than bladder cancer. In this study, we describe the effect of luteolin on a human bladder cancer cell line, T24, in the context of the regulation of p21, thioredoxin-1 (TRX1) and the mechanistic target of rapamycin (mTOR) pathway. Luteolin inhibited cell survival and induced G2/M cell-cycle arrest, p21 up-regulation in both p53 both wild and mutant type cell lines and down-regulation of phospho(p)-S6, which is downstream of mTOR signaling. Luteolin also upregulated TRX1 and reduced intracellular reactive oxygen species production. In a subcutaneous xenograft mouse model using the rat bladder cancer cell line, BC31, tumor volumes were significantly decreased in mice orally administered luteolin compared to control. Immunohistochemical analysis revealed increased p21 and decreased p-S6 expression were induced in the luteolin treatment group. Moreover, in another in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)–induced rat bladder cancer model, the oral administration of luteolin led to a trend in decreased bladder tumor dimension and significantly decreased the Ki67-labeling index and p-S6 expression. Further, the major findings in the metabolism of luteolin suggests both plasma and urine luteolin-3'-O -glucuronide concentrations are strongly associated with the inhibition of cell proliferation and mTOR signaling. Moreover, a significant decrease in the squamous differentiation of bladder cancer is attributed to plasma luteolin-3'-glucuronide concentrations, which is contributed to up-regulation of glutathione peroxidase 2(GPX2) . In conclusion, luteolin, and in particular its metabolized product, may represent another natural product–derived therapeutic agent that acts against bladder cancer by up-regulating p21 and inhibiting mTOR signaling.