ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus-Infected Cell Autophagic Death and Represses Tumor Growth

作者：Dai, Lu; Bai, Aiping; Smith, Charles D.; Rodriguez, Paulo C.; Yu, Fangyou^*; Qin, Zhiqiang^*

来源：Molecular Cancer Therapeutics, 2017, 16(12): 2724-2734.

DOI：10.1158/1535-7163.MCT-17-0485

• PRIMARY EFFUSION LYMPHOMA
• ACTIVE ANTIRETROVIRAL THERAPY
• KAPOSIS-SARCOMA
• CONFERS RESISTANCE
• CERAMIDE SYNTHASES
• ENDOTHELIAL-CELLS
• IN-VITRO
• METALLOTHIONEIN
• HERPESVIRUS
• APOPTOSIS

Kaposi sarcoma-associated herpes virus (KSHV) is the etiologic agent of several malignancies, including Kaposi sarcoma 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 proapoptotic ceramides to antiapoptotic 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 this study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term-infected immortalized endothe-lial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the upregulation 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 was required for the ABC294640-induced autophagic death. By using a Kaposi sarcoma-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.

• 出版日期2017-12
• 单位同济大学附属上海市肺科医院; 同济大学