期刊
MOLECULAR CANCER THERAPEUTICS
卷 16, 期 12, 页码 2724-2734出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-0485
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资金
- DOD Career Development Award [CA140437]
- Louisiana Clinical and Translational Science Center Pilot grant (from NIH) [U54GM104940]
- LSU LIFT2 funding
- NIH [P20-GM121288-01]
- National Natural Science Foundation of China [81472547, 81672924, 81400164, 81772930]
- CDMRP [793839, CA140437] Funding Source: Federal RePORTER
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. (C) 2017 AACR.
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