Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for several human cancers including primary effusion lymphoma (PEL), a rapidly progressive malignancy arising preferentially in immunocompromised patients. With conventional chemotherapy, PEL continues to portend high mortality, dictating the development of novel therapeutic strategies. Sphingosine kinase 2 (SphK2) represents a key gatekeeper for sphingolipid metabolism, responsible for conversion of ceramides to sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to intracellular accumulation of ceramides and induces apoptosis for KSHV-infected PEL cells, while suppressing tumor progression in vivo. In the current study, we sought to determine whether specific ceramide/dh-ceramide species and related ceramide synthases (CerS) impact viability for KSHV-infected PEL cells during targeting of SphK2. We found that several specific ceramide and dihydro(dh)-ceramide species and their associated CerS reduce PEL survival and tumor expansion in vitro and in vivo. Moreover, we found that dhC16-Cer induces PEL apoptosis in part through activation of KSHV lytic gene expression. These data further implicate bioactive sphingolipids in regulation of PEL survival, and provide justification for future studies evaluating clinically relevant ceramide analogs or mimetics for their potential as therapeutic agents for PEL.
Highlights
Sphingolipids are a family of membrane lipids regulating the fluidity and subdomain structure of lipid bilayers [1, 2]
We previously reported that a selective inhibitor of Sphingosine kinase 2 (SphK2), ABC294640, increased cumulative ceramide levels within Kaposi’s sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells [19]
We found that BCBL-1 cells recovered from ascites of ABC294640-treated NOD/SCID mice exhibited increased levels of long-chain ceramide and dh-ceramide species relative to BCBL-1 cells recovered from vehicle-treated control mice (Figure 1D)
Summary
Sphingolipids are a family of membrane lipids regulating the fluidity and subdomain structure of lipid bilayers [1, 2]. Ceramides are composed of a sphingosine base and amide-linked acyl chains of varied length www.impactjournals.com/oncotarget [3]. Endogenous ceramide can be generated via de novo synthesis by ceramide synthases (CerS) [4, 5], or through the metabolism of other complex sphingolipids regulated by specialized enzymes [1, 2, 6]. Bioactive sphingolipids, including ceramides and S1P, act as signaling molecules to regulate apoptosis and tumor cell survival [1]. In contrast to the anti-apoptotic function of S1P, most endogenous long-chain ceramides are thought to induce cell death preferentially [7]. Over the past two decades, targeting bioactive sphingolipids has evolved as a promising therapeutic approach for cancer treatment [10]
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