Abstract 28: Dihydrolipoyl dehydrogenase is a key molecule inducing ferroptotic cell death

Abstract

Ferroptosis is iron-dependent, non-apoptotic cell death from lipid peroxidation. Cystine-glutamate transporter (xCT) and glutathione peroxidase 4 (GPX4) are recognized as the key regulators of ferroptosis. Glutathione depletion via cystine deficiency or inhibition of xCT or GPX4 accumulates cellular lipid peroxidation and ferrous iron, resulting in ferroptosis. Glutamine is an amino acid essential for growth of cancer cells as well as induction of ferroptotic cell death via the production of alpha-ketoglutarate (αKG) from glutaminolysis. However, it is still unclear whether αKG or its relevant metabolic process is engaged in ferroptotic cell death. Therefore, we examined the role of αKG dehydrogenase (αKGDH) in induction of ferroptosis in head and neck cancer (HNC) cells. Cystine-deficient conditioned medium or xCT inhibition with sulfasalazine induced typical ferroptotic cell death, which was prevented by the inhibition of glutaminolysis or αKG production. Next, we focused the dihydrolipoyl dehydrogenase (DLD) and dihydrolipoyl succinyltransferase (DLST), consisting of the E3 and E2 components of αKGDH respectively. Ferroptosis was significantly prevented by genetic inhibition of the DLD but not the DLST, which was rescued by re-insertion of the DLD gene. Cellular reactive oxygen, lipid peroxidation, and ferrous iron accumulation were induced by the increased function of αKGDH, that is mainly the DLD, when αKG was converted to succinate in the tricarboxylic acid cycle. Sulfasalazine did not significantly suppress the in vivo growth of the shDLD-transfected HNC cells but vector control transplanted in nude mice. Taken together, our data support that the DLD is a key molecule inducing ferroptosis in cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Jaewang Lee, Daiha Shin, Jong-Lyel Roh. Dihydrolipoyl dehydrogenase is a key molecule inducing ferroptotic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 28.