ABC294640, a novel sphingosine kinase 2 inhibitor induces oncogenic virus infected cell autophagic death and represses tumor growth

Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of pro-apoptotic ceramides to anti-apoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In the current study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term-infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the up-regulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1, was found to directly regulate LC3B expression and required for the ABC294640-induced autophagic death. By using a KS-like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo, which indicates that targeting sphingolipid metabolism especially SphK2 may represent a promising therapeutic strategy against KSHV-related malignancies.

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