ABC294640, A novel sphingosine kinase 2 inhibitor, induces oncogenic virus–infected cell autophagic death and represses tumor growth

Lu Dai, Aiping Bai, Charles Smith, Paulo C. Rodriguez, Fangyou Yu, Zhiqiang Qin

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 endothelial 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.

Original languageEnglish (US)
Pages (from-to)2724-2734
Number of pages11
JournalMolecular cancer therapeutics
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Autophagy
Primary Effusion Lymphoma
Viruses
Growth
Sphingolipids
Ceramides
Neoplasms
Endothelial Cells
Apoptosis
Oncogenic Viruses
Kaposi's Sarcoma
Nude Mice
Cell Cycle
Up-Regulation
Therapeutics
Cell Proliferation
3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
sphingosine kinase
HIV
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Dai, Lu ; Bai, Aiping ; Smith, Charles ; Rodriguez, Paulo C. ; Yu, Fangyou ; Qin, Zhiqiang. / ABC294640, A novel sphingosine kinase 2 inhibitor, induces oncogenic virus–infected cell autophagic death and represses tumor growth. In: Molecular cancer therapeutics. 2017 ; Vol. 16, No. 12. pp. 2724-2734.
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abstract = "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 endothelial 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.",
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ABC294640, A novel sphingosine kinase 2 inhibitor, induces oncogenic virus–infected cell autophagic death and represses tumor growth. / Dai, Lu; Bai, Aiping; Smith, Charles; Rodriguez, Paulo C.; Yu, Fangyou; Qin, Zhiqiang.

In: Molecular cancer therapeutics, Vol. 16, No. 12, 01.12.2017, p. 2724-2734.

Research output: Contribution to journalArticle

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T1 - ABC294640, A novel sphingosine kinase 2 inhibitor, induces oncogenic virus–infected cell autophagic death and represses tumor growth

AU - Dai, Lu

AU - Bai, Aiping

AU - Smith, Charles

AU - Rodriguez, Paulo C.

AU - Yu, Fangyou

AU - Qin, Zhiqiang

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