ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus-Infected Cell Autophagic Death and Represses Tumor Growth.
ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus-Infected Cell Autophagic Death and Represses Tumor Growth.
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ABC294640，一种新型鞘氨醇激酶 2 抑制剂，诱导致癌病毒感染的细胞自噬性死亡并抑制肿瘤生长
DOI：
10.1158/1535-7163.mct-17-0485
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发表时间：
2017-12
影响因子：
5.7
通讯作者：
Qin Z
中科院分区：
文献类型：
--
作者：
Dai L;Bai A;Smith CD;Rodriguez PC;Yu F;Qin Z
卡波西肉瘤相关疱疹病毒（KSHV）是几种恶性肿瘤的病原体，包括卡波西肉瘤（KS）和原发性渗出性淋巴瘤（PEL），这些肿瘤优先发生在HIV+患者中，缺乏有效的治疗。鞘氨醇激酶2（SphK 2）是鞘脂代谢中的关键因子，负责将促凋亡神经酰胺转化为抗凋亡鞘氨醇-1-磷酸（S1 P）。我们以前已经证明，使用一种新的选择性抑制剂ABC 294640靶向SphK 2，导致细胞内神经酰胺的积累，并诱导KSHV感染的原代内皮细胞和PEL肿瘤细胞凋亡，但在未感染的细胞中不诱导凋亡。在目前的研究中，我们发现，ABC 294640诱导自噬性死亡，而不是凋亡在KSHV长期感染的永生化内皮细胞系，TIVE-LTC，但不是在未感染的TIVE细胞，通过上调LC 3B蛋白。转录组学分析表明，与细胞应激反应、细胞周期/增殖和细胞代谢过程相关的许多基因在暴露于ABC 294640的TIVE-LTC中被改变。Egr-1被发现直接调节LC 3B的表达，并且是ABC 294640诱导的自噬性死亡所必需的。通过使用具有TIVE-LTC的KS样裸鼠模型，我们发现ABC 294640治疗显著抑制KSHV诱导的体内肿瘤生长，这表明靶向鞘脂代谢尤其是SphK 2可能代表针对KSHV相关恶性肿瘤的有希望的治疗策略。
Kaposi’s Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi’s Sarcoma (KS) 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 pro-apoptotic ceramides to anti-apoptotic 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 the current 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 up-regulation 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 required for the ABC294640-induced autophagic death. By using a KS-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.