Abstract 5104: Isorhapontigenin (ISO) inhibits cancer invasion by enhancing FOXO1 transcription through targeting STAT1 phosphorylation at Tyr701

Abstract

Abstract Muscle invasion of bladder cancer can progress to life threatening metastases. Isorhapontigenin (ISO) is a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, which has been used for centuries as treatment for several cancers including bladder cancer. However, nothing is known whether ISO possesses an inhibitory effect on invasion in human cancers. Here, we found that 10 to 20 mmol/L of ISO, which were relevant to in vivo study, inhibited human bladder cancer cell invasion accompanied by up-regulation of the forkhead box class O1 (FOXO1) mRNA transcription. Accordingly, FOXO1 was significantly down-regulated in invasive human bladder cancer tissues, and forced expression of FOXO1 specifically suppressed invasion of human bladder cancer cells. Moreover, knockdown of FOXO1 expression abolished the ISO inhibition of invasion. Further studies showed that increased FOXO1 transcription was accompanied by reduction of STAT1 phosphorylation at Tyr701, and repressing STAT1 phosophorylation by the overexpression of dominant negative STAT1 could mimic the effect of ISO treatment on FOXO1 transcription, while the mutation of STAT1's binding site in the FOXO1 promoter profoundly impaired ISO-induced up-regulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector mediating its effect on bladder cancer invasion. These findings not only provide a novel insight into the understanding of underlying mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such invasion through targeting the STAT1-FOXO1-MMP2 axis. Citation Format: Lei Xue, Guosong Jiang, Jingxia Li, Chuanshu Huang. Isorhapontigenin (ISO) inhibits cancer invasion by enhancing FOXO1 transcription through targeting STAT1 phosphorylation at Tyr701. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5104. doi:10.1158/1538-7445.AM2015-5104