Developing new ceramide analogs and identifying novel sphingolipid controlled genes against a virus-associated lymphoma

Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy, usually infected by Kaposi's sarcoma-associated herpesvirus (KSHV), one of human oncogenic viruses. Currently, there is no specific treatment for PEL, therefore developing new therapies is of high importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cells survival. To further develop sphingolipid metabolism targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes, and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death, and identified a subset of novel cellular genes including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.