Sphingosine kinase (SPHK) is overexpressed by a variety of
cancers, and its phosphorylation of
sphingosine results in accumulation of
sphingosine-1-phosphate (S1P) and activation of antiapoptotic signal transduction. Existing data indicate a role for S1P in viral pathogenesis, but roles for SPHK and S1P in virus-associated
cancer progression have not been defined. Rare pathologic variants of
diffuse large B-cell lymphoma arise preferentially in the setting of
HIV infection, including
primary effusion lymphoma (PEL), a highly mortal
tumor etiologically linked to the Kaposi's sarcoma-associated herpesvirus (KSHV). We have found that
ABC294640, a novel clinical-grade small molecule selectively targeting SPHK (SPHK2 >> SPHK1), induces dose-dependent
caspase cleavage and apoptosis for KSHV(+) patient-derived PEL cells, in part through inhibition of constitutive signal transduction associated with PEL cell proliferation and survival. These results were validated with induction of PEL cell apoptosis using SPHK2-specific
siRNA, as well as confirmation of
drug-induced SPHK inhibition in PEL cells with dose-dependent accumulation of proapoptotic
ceramides and reduction of intracellular S1P. Furthermore, we demonstrate that systemic administration of
ABC294640 induces
tumor regression in an established human PEL xenograft model. Complimentary ex vivo analyses revealed suppression of signal transduction and increased KSHV lytic gene expression within
drug-treated
tumors, with the latter validated in vitro through demonstration of dose-dependent viral lytic gene expression within PEL cells exposed to
ABC294640. Collectively, these results implicate interrelated mechanisms and SPHK2 inhibition in the induction of PEL cell death by
ABC294640 and rationalize evaluation of
ABC294640 in clinical trials for the treatment of KSHV-associated
lymphoma.