Abstract 588: Silencing of MnSOD attenuates ATRA-induced neurofilament expression in neuroblastoma cells

Abstract

Abstract Differentiation therapy with retinoids is a means to treat high-risk neuroblastoma patients when the tumor has recurred after initial attempts of removal by surgery, radiation, and/ or chemotherapy. A metabolite of Vitamin A, all-trans retinoic acid (ATRA) is the main signaling retinoid in vivo and one of the most potent differentiation inducers for human neuroblastoma in vitro. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that converts the superoxide anion to hydrogen peroxide. Previously we have reported that ATRA increased MnSOD expression and activity in SK-N-SH neuroblastoma cells. However, our current study suggests that this upregulation may limit the ability of ATRA to induce differentiation. Treatment with ATRA upregulated the expression of neurofilament (an early marker of neuronal differentiation) as early as 48 hrs. Although MnSOD activity was not significantly increased by ATRA until 72 hrs, silencing of the MnSOD gene with siRNA enhanced neurofilament expression over that of cells infected with a control siRNA construct at 48 hrs. This suggests that even basal levels of MnSOD activity can attenuate an early marker of differentiation. We also demonstrated that ATRA decreased catalase expression and increased dichlorofluoroscein fluorescence, suggesting an increase in hydrogen peroxide. Therefore, these data suggest that rather than being scavenged by catalase, hydrogen peroxide may remain present in the cell after ATRA treatment to also limit the differentiation potential of the cells. Taken together, it is apparent that the alteration of redox status by retinoids may contribute to the modulation of genes which are involved in differentiation. (Funding: Centers for Biomedical Research Excellence 1P20RR020180 (KKK) and 5P20RR016477; WV-INBRE 5P20RR016477; WV-NASA 91-175B). 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 588. doi:10.1158/1538-7445.AM2011-588