Targeting sphingosine kinase by ABC294640 induces KSHV-infected endothelial cell autophagic death

KSHV is a principal causative agent of Kaposi's Sarcoma (KS). Despite this knowledge about the close relationship between sphingolipid metablism and solid tumors development, the role of sphingolipid metablism in KSHV-related malignancies remains mostly unclear. We report that targeting sphingosine kinase 2 (SphK2) by a selective inhibitor, ABC294640, significantly induces KSHV+ TIVE-LTC autophagic death. By using microarray analysis, we have identified the global gene profile affected by ABC294640 within KSHV+ TIVE-LTC and several novel “druggable” candidates closely related to cancer cell survival/growth. Finally, we found that targeting TIVE-LTC by ABC294640 effectively suppressed KSHV tumorigenicity by using a KS-like nude mice model. TIVE-LTC were treated with vehicle control or SphK2 inhibitor ABC294640 (60 µM) for 24 h, and the gene expression signature was compared to respective vehicle controls

卡波西肉瘤疱疹病毒（Kaposi's Sarcoma-associated Herpesvirus, KSHV）是卡波西肉瘤（Kaposi's Sarcoma, KS）的主要致病病原体。尽管学界已明确鞘脂代谢（sphingolipid metabolism）与实体肿瘤的发生发展存在紧密关联，但鞘脂代谢在KSHV相关恶性肿瘤中的作用仍未得到充分阐明。本研究报道，利用选择性抑制剂ABC294640靶向鞘氨醇激酶2（sphingosine kinase 2, SphK2），可显著诱导KSHV阳性TIVE-LTC细胞发生自噬性死亡。通过基因芯片分析（microarray analysis），我们明确了KSHV阳性TIVE-LTC细胞中受ABC294640调控的全局基因表达谱，并筛选出数个与癌细胞存活、增殖密切相关的新型可靶向药物候选靶点。最后，我们借助卡波西肉瘤样裸小鼠模型证实，ABC294640靶向TIVE-LTC细胞可有效抑制KSHV相关肿瘤的致瘤性。将TIVE-LTC细胞以溶剂对照组（vehicle control）或SphK2抑制剂ABC294640（60 µM）处理24小时后，我们将其基因表达特征与相应溶剂对照组进行了对比分析。