Mansat V, Laurent G, Levade T, Bettaïeb A, Jaffrézou J P
Contrat Jeune Formation, Institut National de la Santé et de la Recherche Médicale 9503, Centre Claudius Régaud, Toulouse, France.
Cancer Res. 1997 Dec 1;57(23):5300-4.
To address the role of protein kinase C (PKC) in the regulation of ceramide production, we evaluated the impact of the PKC activators 12-O-tetradecanoylphorbol-13-acetate and phosphatidylserine on the apoptotic signaling pathway triggered by the chemotherapeutic drug daunorubicin. Treatment of U937 and HL-60 cells with 0.5-1 microM daunorubicin induced a greater than 30% activation of neutral sphingomyelinase activity within 4-10 min with concomitant sphingomyelin hydrolysis and ceramide generation. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate and phosphatidylserine inhibited daunorubicin-induced neutral sphingomyelinase activation, sphingomyelin hydrolysis, ceramide generation, and apoptosis. The apoptotic response could be restored by the addition of 25 microM cell-permeant C6-ceramide. In conclusion, PKC emerges as a potentially critical negative regulator of the anthracycline-activated sphingomyelin-ceramide apoptotic pathway.
为了研究蛋白激酶C（PKC）在神经酰胺生成调节中的作用，我们评估了PKC激活剂十四酰佛波醇乙酯和磷脂酰丝氨酸对化疗药物柔红霉素触发的凋亡信号通路的影响。用0.5 - 1微摩尔柔红霉素处理U937和HL - 60细胞，在4 - 10分钟内诱导中性鞘磷脂酶活性激活超过30%，同时伴有鞘磷脂水解和神经酰胺生成。十四酰佛波醇乙酯和磷脂酰丝氨酸激活PKC可抑制柔红霉素诱导的中性鞘磷脂酶激活、鞘磷脂水解、神经酰胺生成及凋亡。加入25微摩尔细胞渗透性C6 - 神经酰胺可恢复凋亡反应。总之，PKC成为蒽环类药物激活的鞘磷脂 - 神经酰胺凋亡途径的潜在关键负调节因子。
