Novel ceramide compound, candidate for head and neck cancer treatment, induces mitophagy through ceramide signaling

Ceramide is a bioactive sphingolipid that is involved in signaling pathways regulating cancer cell death and tumor growth. In several types of cells, the ceramide synthesis or accumulation upon cellular stress is known to bring about one of the ceramide-induced cancer cell death mechanism; lethal mitophagy. Mitochondria-targeted ceramide analogs constitute one of the anticancer strategies that are applied to induce lethal mitophagy in cancer cells. In this study, we revealed that LCL768, a new pyridinium ceramide analog conjugated with selenium, induced lethal mitophagy in Head and Neck Squamos Cell Carcinoma. Mechanistically, LCL768 was implicated for Drp1 activation through nitrosylation at C644. Also, the activation of Drp1 regulates CerS1 trafficking to mitochondria for CerS1/C18-ceramide mediated signaling. Besides, our data demonstrated that LCL768 along with endogenous C18-ceramide accumulated mainly in mitochondria. This accumulation of LCL768 significantly impaired the mitochondrial functions in HNSCC. Moreover, LCL768 resulted in ceramide-mediated growth inhibition in xenograft-derived tumors and also mitophagy for both xenograft-derived tumors and 3D patient organoids. Overall, this study reveals a novel mechanism for LCL768 in the regulation of ceramide-mediated mitophagy in HNSCC.