Ceramides promote apoptosis for virus-infected lymphoma cells through induction of ceramide synthases and viral lytic gene expression.
Ceramides promote apoptosis for virus-infected lymphoma cells through induction of ceramide synthases and viral lytic gene expression.
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神经酰胺通过诱导神经酰胺合酶和病毒裂解基因表达促进病毒感染的淋巴瘤细胞凋亡
DOI：
10.18632/oncotarget.4759
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Parsons C
中科院分区：
文献类型：
--
作者：
Dai L;Trillo-Tinoco J;Bai A;Chen Y;Bielawski J;Del Valle L;Smith CD;Ochoa AC;Qin Z;Parsons C
卡波西肉瘤相关疱疹病毒(KSHV)是包括原发性渗出性淋巴瘤(PEL)在内的几种人类癌症的病原体，PEL是一种快速进展的恶性肿瘤，优先发生在免疫功能低下的患者中。对于常规化疗，PEL继续预示着高死亡率，这决定了新治疗策略的发展。鞘氨醇激酶2(SphK2)是鞘磷脂代谢的关键守门人，负责神经酰胺向鞘氨醇-1-磷酸(S1P)的转化。我们先前已经证明，使用一种新的选择性抑制剂ABC294640靶向SphK2，会导致神经酰胺在细胞内积累，并诱导KSHV感染的PEL细胞凋亡，同时抑制体内肿瘤的进展。在目前的研究中，我们试图确定在靶向SphK2的过程中，特定的神经酰胺/dh-神经酰胺种类和相关的神经酰胺合成酶(CER)是否会影响KSHV感染的PEL细胞的存活。我们发现，在体外和体内，几种特定的神经酰胺和二氢(Dh)-神经酰胺种类及其相关的CER降低了PEL的存活率和肿瘤的扩展。此外，我们还发现dhC16-Cer通过激活KSHV裂解基因的表达部分地诱导了PEL的凋亡。这些数据进一步表明，具有生物活性的鞘磷脂参与了PEL生存的调节，并为未来评估临床相关神经酰胺类似物或模拟物作为PEL治疗剂的潜力提供了依据。
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for several human cancers including primary effusion lymphoma (PEL), a rapidly progressive malignancy arising preferentially in immunocompromised patients. With conventional chemotherapy, PEL continues to portend high mortality, dictating the development of novel therapeutic strategies. Sphingosine kinase 2 (SphK2) represents a key gatekeeper for sphingolipid metabolism, responsible for conversion of ceramides to sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to intracellular accumulation of ceramides and induces apoptosis for KSHV-infected PEL cells, while suppressing tumor progression in vivo. In the current study, we sought to determine whether specific ceramide/dh-ceramide species and related ceramide synthases (CerS) impact viability for KSHV-infected PEL cells during targeting of SphK2. We found that several specific ceramide and dihydro(dh)-ceramide species and their associated CerS reduce PEL survival and tumor expansion in vitro and in vivo. Moreover, we found that dhC16-Cer induces PEL apoptosis in part through activation of KSHV lytic gene expression. These data further implicate bioactive sphingolipids in regulation of PEL survival, and provide justification for future studies evaluating clinically relevant ceramide analogs or mimetics for their potential as therapeutic agents for PEL.