Mengubas K, Riordan F A, Bravery C A, Lewin J, Owens D L, Mehta A B, Hoffbrand A V, Wickremasinghe R G
Department of Hematology, Royal Free and University College School of Medicine, London, UK.
Oncogene. 1999 Apr 15;18(15):2499-506. doi: 10.1038/sj.onc.1202622.
Synthetic ceramides induce apoptotic death of Jurkat and HL60 leukaemia cell lines. By contrast we show here that ceramide induces non-apoptotic killing of malignant cells from patients with B-chronic lymphocytic leukaemia (B-CLL) and of normal B lymphocytes. The protein phosphatase inhibitor okadaic acid readily induces apoptosis of B-CLL cells, indicating that this death pathway is fully functional in these cells. The ability of ceramide to activate the apoptotic protease caspase 3 in HL60 cells but not in B-CLL cells, as well as the lack of correlation of ceramide-mediated killing of different B-CLL isolates with expression of the apoptosis-regulating proteins bcl-2 and bax reinforce the conclusion that ceramide killing of B-CLL cells is by a non-apoptotic mechanism. Fludarabine treatment or gamma-irradiation of B-CLL cells resulted in ceramide elevation and in killing by both apoptotic and non-apoptotic mechanisms, suggesting that a ceramide-triggered non-apoptotic mechanism may play a role in the killing of these cells. Therefore, the results here show that ceramide can induce either apoptotic or non-apoptotic death, depending on the cellular context. The inability of synthetic dihydroceramide to kill B-CLL cells or normal B lymphocytes suggests that non-apoptotic killing by ceramide is via interaction with a specific, but unidentified, cellular target.
合成神经酰胺可诱导Jurkat和HL60白血病细胞系发生凋亡性死亡。相比之下，我们在此表明神经酰胺可诱导B慢性淋巴细胞白血病（B-CLL）患者的恶性细胞以及正常B淋巴细胞发生非凋亡性杀伤。蛋白磷酸酶抑制剂冈田酸很容易诱导B-CLL细胞凋亡，这表明该死亡途径在这些细胞中功能完全正常。神经酰胺在HL60细胞中可激活凋亡蛋白酶caspase 3，但在B-CLL细胞中却不能，以及神经酰胺介导的不同B-CLL分离株的杀伤作用与凋亡调节蛋白bcl-2和bax的表达缺乏相关性，这些都强化了以下结论：神经酰胺对B-CLL细胞的杀伤是通过非凋亡机制。氟达拉滨治疗或γ射线照射B-CLL细胞会导致神经酰胺水平升高，并通过凋亡和非凋亡机制进行杀伤，这表明神经酰胺触发的非凋亡机制可能在这些细胞的杀伤中起作用。因此，此处的结果表明，根据细胞环境的不同，神经酰胺可诱导凋亡性或非凋亡性死亡。合成二氢神经酰胺无法杀伤B-CLL细胞或正常B淋巴细胞，这表明神经酰胺的非凋亡性杀伤是通过与一个特定但未明确的细胞靶点相互作用实现的。
