A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis
A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis
复制标题
DOI：
10.1074/jbc.m209044200
复制
发表时间：
2003-01-17
影响因子：
4.8
通讯作者：
Deng, XM
中科院分区：
文献类型：
--
作者：
Mai, HQ;May, WS;Deng, XM
尼古丁不仅是烟草的主要成分，也是一种生存激动剂，可以抑制包括化疗药物在内的多种刺激诱导的细胞凋亡。然而，尼古丁抑制细胞凋亡的细胞内机制尚不清楚。Bcl2是一种有效的抗凋亡蛋白和肿瘤启动子，在小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）细胞中均有表达。尼古丁可能通过调节Bcl2刺激细胞存活。在这里，我们报道尼古丁可以诱导Bcl2在丝氨酸70位点的磷酸化，这与SCLC H82细胞在化疗药物（如顺铂或VIP-16）治疗后表达野生型而不是磷酸化缺陷的S70A突变体Bcl2的存活时间延长有关。尼古丁诱导激活PKCalpha和MAPKs ERK1和ERK2，这是生理上的Bcl2激酶。此外，特异性磷脂酶C （PLC）抑制剂ET-18-OCH3可阻断尼古丁刺激的Bcl2磷酸化并促进细胞凋亡，提示PLC可能参与尼古丁激活Bcl2激酶。通过遗传方法，功能获得型S70E突变体，模仿灵活环域中Ser（70）位点的磷酸化，有效地增强了SCLC细胞的化学耐药。因此，尼古丁诱导的细胞存活结果，至少在一定程度上，来自一个涉及Bcl2磷酸化的机制。因此，Bcl2表达的肺癌的新治疗策略可能通过抑制多种上游尼古丁激活途径来消除Bcl2的抗凋亡活性。
Nicotine is not only a major component in tobacco but is also a survival agonist that inhibits apoptosis induced by diverse stimuli including chemotherapeutic drugs. However, the intracellular mechanism(s) involved in nicotine suppression of apoptosis is unclear. Bcl2 is a potent antiapoptotic protein and tumor promotor that is expressed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. It is possible that nicotine may regulate Bcl2 to stimulate cell survival. Here we report that nicotine can induce Bcl2 phosphorylation exclusively at the serine 70 site in association with prolonged survival of SCLC H82 cells expressing wild-type but not the phosphorylation-deficient S70A mutant Bcl2 after treatment with chemotherapeutic agents (i.e. cisplatin or VIP-16). Nicotine induces activation of PKCalpha and the MAPKs ERK1 and ERK2, which are physiological Bcl2 kinases. Furthermore, ET-18-OCH3, a specific phospholipase C (PLC) inhibitor, blocks nicotine-stimulated Bcl2 phosphorylation and promotes apoptosis, suggesting that PLC may be involved in nicotine activation of Bcl2 kinases. Using a genetic approach, the gain-of-function S70E mutant, which mimics Ser(70) site phosphorylation in the flexible loop domain, potently enhances chemoresistance in SCLC cells. Thus, nicotine-induced cell survival results, at least in part, from a mechanism that involves Bcl2 phosphorylation. Therefore, novel therapeutic strategies for lung cancer in which Bcl2 is expressed may be used to abrogate the anti-apoptotic activity of Bcl2 by inhibiting multiple upstream nicotine-activated pathways.