Sánchez Ana Maria, Malagarie-Cazenave Sophie, Olea Nuria, Vara Diana, Chiloeches Antonio, Díaz-Laviada Inés
Department of Biochemistry and Molecular Biology, School of Medicine, University of Alcalá, 28871, Alcalá de Henares, Madrid, Spain.
Apoptosis. 2007 Nov;12(11):2013-24. doi: 10.1007/s10495-007-0119-z.
Numerous studies have recently focused on the anticarcinogenic, antimutagenic, or chemopreventive activities of the main pungent component of red pepper, capsaicin (N-vanillyl-8-methyl-1-nonenamide). We have previously shown that, in the androgen-independent prostate cancer PC-3 cells, capsaicin inhibits cell growth and induces apoptosis through reactive oxygen species (ROS) generation [Apoptosis 11 (2006) 89-99]. In the present study, we investigated the signaling pathways involved in the antiproliferative effect of capsaicin. Here, we report that capsaicin apoptotic effect was mediated by ceramide generation which occurred by sphingomyelin hydrolysis. Using siRNA, we demonstrated that N-SMase expression is required for the effect of capsaicin on prostate cell viability. We then investigated the role of MAP kinase cascades, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, in the antiproliferative effect of capsaicin, and we confirmed that capsaicin could activate ERK and JNK but not p38 MAPK. Pharmacological inhibition of JNK kinase, as well as inhibition of ROS by the reducing agent N-acetylcysteine, prevented ceramide accumulation and capsaicin-induced cell death. However, inhibition of ceramide accumulation by the SMase inhibitor D609 did not modify JNK activation. These data reveal JNK as an upstream regulator of ceramide production. Capsaicin-promoted activation of ERK was prevented with all the inhibitors tested. We conclude that capsaicin induces apoptosis in PC-3 cells via ROS generation, JNK activation, ceramide accumulation, and second, ERK activation.
最近，众多研究聚焦于红辣椒的主要辛辣成分辣椒素（N-香草基-8-甲基-1-壬酰胺）的抗癌、抗诱变或化学预防活性。我们之前已经表明，在雄激素非依赖性前列腺癌PC-3细胞中，辣椒素通过产生活性氧（ROS）抑制细胞生长并诱导凋亡[《细胞凋亡》11（2006年）89 - 99页]。在本研究中，我们调查了参与辣椒素抗增殖作用的信号通路。在此，我们报告辣椒素的凋亡作用是由鞘磷脂水解产生神经酰胺介导的。使用小干扰RNA（siRNA），我们证明N-鞘磷脂酶（N-SMase）表达是辣椒素对前列腺细胞活力产生作用所必需的。然后，我们研究了丝裂原活化蛋白激酶（MAPK）级联反应、细胞外信号调节蛋白激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38 MAPK在辣椒素抗增殖作用中的作用，并且我们证实辣椒素可激活ERK和JNK，但不能激活p38 MAPK。JNK激酶的药理学抑制以及还原剂N-乙酰半胱氨酸对ROS的抑制可防止神经酰胺积累和辣椒素诱导的细胞死亡。然而，鞘磷脂酶抑制剂D609对神经酰胺积累的抑制并未改变JNK激活。这些数据揭示JNK是神经酰胺产生的上游调节因子。用所有测试的抑制剂均可阻止辣椒素促进的ERK激活。我们得出结论，辣椒素通过产生活性氧、激活JNK、积累神经酰胺以及其次激活ERK来诱导PC-3细胞凋亡。
