Abstract 3791: Sulphoraphane inhibits STAT3 and its related genes in Du 145 cancer cells

Sulforaphane is a naturally occurring isothiocyanate compound mainly found in cruciferous vegetables. Sulforaphane has demonstrated cancer chemopreventive activities in a number of organ sites, including prostate. Mechanistic investigations have shown that SFN induces caspase-mediated apoptosis that is mediated through a rapid intracellular ROS generation. Since STAT3 signaling is crucial for cancer cell survival and ROS has been linked to inactivation of this transcriptional factor, we hypothesized that STAT3 may be an important target for SFN. Here, we investigated the effect of sulforaphane on the regulation of STAT3 in association of ROS in Du145 prostate cancer cells. We first confirmed that sulforaphane induced apoptosis by activation of caspase 8, 9, and 3, PARP cleavage and increase of TUNEL positive cells in Du145 cells, which were preceded for many hours by the increase of intracellular ROS, peaking at 30 minutes of exposure. We demonstrate for the first time that sulforaphane suppressed constitutive STAT3 activation and DNA-binding of STAT3 in a time- and dose-dependent manner in Du145 cells. These actions were also found in U266 multiple myeloma cells and U937 lymphoma cells. In addition, sulforaphane down-regulated the expression of STAT3-related genes such as bcl-2, bcl-xL, survivin, cyclin D1, and VEGF in Du145 cells. Furthermore, sulforaphane cross-linked JAK2, the upstream kinase of STAT3, in a time- and dose-dependent manner. Thiol-reducing agent dithiothreitol (DTT) reversed the inactivation of STAT3 and JAK2 induced by sulforaphane. Interestingly, N-acetyl cysteine (NAC), which leads to increased intracellular GSH synthesis, reversed the molecular patterns of PARP cleavage and inactivation of JAK2 and STAT3 induced by sulphoraphane. Taken together, these findings suggest that sulforaphane exposure leads to a rapid generation of ROS in Du145 cells and inhibition of JAK2/STAT3 pathway, followed by caspase-mediated apoptosis. Our data suggest that the JAK2/STAT3 pathway may be a novel target of SFN contributing to apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3791.