Regulation of ceramide by the novel synthetic retinoid ST1926-induced cell death in HTLV-1 transformed and malignant T Cells -

Abstract

Adult T cell Leukemia-lymphoma (ATL) is an aggressive malignancy caused by human T cell lymphotropic virus type 1 (HTLV-1). The oncoprotein Tax maintains viral persistence and pathogenesis and plays a crucial role in disease development. Because of resistance to chemotherapy, ATL carries a poor prognosis, which imposes a need for alternative therapies. ST1926 (E-3-(40-Hydroxy-30-adamantylbiphenyl-4-yl) acrylic acid) is a novel and orally bioavailable synthetic retinoid that has entered Phase I clinical trials. ST1926 has shown potent apoptotic activities and anticancer properties in several cancer models that are resistant to natural retinoids such as all-trans retinoic acid (ATRA). We demonstrated that pharmacologically achievable concentrations of ST1926 induced major cell growth inhibition in HTLV-1 positive and negative malignant T cells as well as in primary ATL cells, while no effect was detected in resting or activated normal lymphocytes. ST1926 induced massive apoptosis and upregulated p53 proteins in malignant T cells, while it caused an early reduction of Tax proteins in HTLV-1 positive cells.Over the past two decades, studies have established ceramide as a potent lipid tumor-suppressor mediating multiple signaling pathways that ultimately determine cell fate response such as cell cycle arrest, apoptosis, and differentiation. The aim of the present study was to investigate the mechanism by which ST1926 regulates ceramide metabolism in HTLV-1 positive and negative malignant T cells. Interestingly, pharmacologically achievable concentrations of ST1926 caused early dose-dependent increases in ceramide levels in both cell types which preceded ST1926-induced growth suppression. ST1926 induced de novo ceramide synthesis in HTLV-1 positive and negative malignant cells and an earlier reduction of Tax protein levels in HTLV-1 positive cells. Most importantly, high-throughput sphingolipidomics analysis of ST1926-treated malignant T cells revealed pronounced accumulation of ceramide versus dihydrocerami