S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism
S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism
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DOI：
10.1038/cddis.2011.3
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发表时间：
2011-02-01
影响因子：
9
通讯作者：
Saba, J. D.
中科院分区：
文献类型：
--
作者：
Kumar, A.;Oskouian, B.;Saba, J. D.
电离辐射（IR）对正常人体细胞的伤害性后果和癌细胞的获得性辐射抗性代表了癌症放射治疗的局限性。IR诱导DNA损伤反应途径，其协调细胞周期停滞、DNA修复或凋亡，使得被照射的细胞被修复或消除。同时和独立的DNA损伤，IR激活酸性鞘磷脂酶（ASMase），产生神经酰胺，从而促进辐射诱导的细胞凋亡。然而，神经酰胺也可以被代谢为鞘氨醇-1-磷酸（S1 P），其矛盾地作为辐射防护剂。因此，鞘脂代谢是一个放射敏感性支点，这一概念得到了耐IR癌细胞遗传证据的支持。S1 P裂解酶（SPL）催化鞘脂代谢最后一步中S1 P的不可逆降解。我们表明，SPL调节DNA修复的动力学，从G2期细胞周期停滞的恢复速度和IR后的凋亡程度。SPL通过一种新的反馈机制，放大应力诱导的神经酰胺积累，和下调/抑制SPL或ASMase防止过早的细胞周期进展和有丝分裂死亡。此外，口服SPL抑制剂的小鼠暴露于致死剂量的全身IR后延长其生存期。我们的研究结果表明SPL是ASMase，G2检查点和DNA修复的调节剂和一个新的目标辐射防护。Cell Death and Disease（2011）2，e119; doi：10.1038/cddis.2011.3; 2011年2月10日在线发表
The injurious consequences of ionizing radiation (IR) to normal human cells and the acquired radioresistance of cancer cells represent limitations to cancer radiotherapy. IR induces DNA damage response pathways that orchestrate cell cycle arrest, DNA repair or apoptosis such that irradiated cells are either repaired or eliminated. Concomitantly and independent of DNA damage, IR activates acid sphingomyelinase (ASMase), which generates ceramide, thereby promoting radiation-induced apoptosis. However, ceramide can also be metabolized to sphingosine-1-phosphate (S1P), which acts paradoxically as a radioprotectant. Thus, sphingolipid metabolism represents a radiosensitivity pivot point, a notion supported by genetic evidence in IR-resistant cancer cells. S1P lyase (SPL) catalyzes the irreversible degradation of S1P in the final step of sphingolipid metabolism. We show that SPL modulates the kinetics of DNA repair, speed of recovery from G2 cell cycle arrest and the extent of apoptosis after IR. SPL acts through a novel feedback mechanism that amplifies stress-induced ceramide accumulation, and downregulation/inhibition of either SPL or ASMase prevents premature cell cycle progression and mitotic death. Further, oral administration of an SPL inhibitor to mice prolonged their survival after exposure to a lethal dose of total body IR. Our findings reveal SPL to be a regulator of ASMase, the G2 checkpoint and DNA repair and a novel target for radioprotection. Cell Death and Disease ( 2011) 2, e119; doi: 10.1038/cddis.2011.3; published online 10 February 2011