Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF gene superfamily that induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it can selectively induce apoptosis in many types of transformed cells. Nevertheless, some bladder cancer cells are particularly resistant to the effects of TRAIL. Here, we report that in combination with the sulforaphane, exposure to TRAIL induced apoptosis in TRAIL-resistant bladder cancer cells. The increased apoptosis by combined treatment with sulforaphane and TRAIL was associated with the marked increased activation of caspases and cleavage of Bid proteins. However, siRNA-mediated silencing of Bid reduced the sensitizing effect of sulforaphane in TRAIL-induced apoptosis and loss of mitochondrial membrane potential (MMP), as did caspase inhibitors, but increased cell survival. The data also indicated that following exposure to sulforaphane, DR5 proteins were up-regulated and knockdown of DR5 expression by siRNA attenuated sulforaphane plus TRAIL-induced apoptosis. In addition, following exposure to sulforaphane, the levels of pAkt proteins were significantly down-regulated without the alteration of whole Bid expression, and inhibition of pAkt by LY294002 increased sulforaphane plus TRAIL-induced apoptosis. In summary, our results indicate that treatment with a combination of TRAIL and sulforaphane may be a safe strategy for treatment of TRAIL-resistant bladder cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4103. doi:10.1158/1538-7445.AM2011-4103