Protein kinase Cι promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of μ- and m-calpains
Protein kinase Cι promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of μ- and m-calpains
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DOI：
10.1074/jbc.m510721200
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发表时间：
2006-02-17
影响因子：
4.8
通讯作者：
Deng, XM
中科院分区：
文献类型：
--
作者：
Xu, LJ;Deng, XM
尼古丁是香烟烟雾中的主要成分，可激活生长促进途径，促进肺癌的发展。然而，尚不清楚尼古丁是否会影响细胞运动以促进肿瘤转移。在这里，我们发现尼古丁通过激活蛋白激酶 C iota (PKC iota) 有效诱导 mu-和 m-钙蛋白酶磷酸化，这与人肺癌细胞的加速迁移和侵袭有关。纯化的 PKC iota 在体外直接磷酸化 mu-和 m-钙蛋白酶。 PKC iota 的过度表达会导致体内 mu- 和 m-钙蛋白酶的磷酸化增加。尼古丁还会诱导 c-Src 的激活，c-Src 是一种已知的 PKC iota 上游激酶。用α(7)烟碱乙酰胆碱受体抑制剂α-金环蛇毒素处理细胞可以阻断尼古丁诱导的钙蛋白酶磷酸化，抑制钙蛋白酶活性、伤口愈合、细胞迁移和侵袭，表明尼古丁诱导的钙蛋白酶磷酸化至少部分通过涉及上游α(7)烟碱乙酰胆碱受体的信号通路发生。有趣的是，通过 RNA 干扰消除 PKC iota 会抑制尼古丁诱导的钙蛋白酶磷酸化、钙蛋白酶活性、细胞迁移和侵袭，表明 PKC iota 是尼古丁介导的细胞运动信号传导的必要组成部分。重要的是，尼古丁有效诱导肺癌细胞将 mu-和 m-钙蛋白酶分泌到培养基中，这可能具有裂解细胞外基质中的底物的潜力。这些发现揭示了 PKC iota 作为尼古丁激活的生理性钙蛋白酶激酶的新作用，可直接磷酸化和激活钙蛋白酶，从而增强人肺癌细胞的迁移和侵袭。
Nicotine is a major component in cigarette smoke that activates the growth-promoting pathways to facilitate the development of lung cancer. However, it is not clear whether nicotine affects cell motility to facilitate tumor metastasis. Here we discovered that nicotine potently induces phosphorylation of both mu- and m-calpains via activation of protein kinase C iota( PKC iota), which is associated with accelerated migration and invasion of human lung cancer cells. Purified PKC iota directly phosphorylates mu- and m-calpains in vitro. Overexpression of PKC iota results in increased phosphorylation of both mu- and m-calpains in vivo. Nicotine also induces activation of c-Src, which is a known PKC iota upstream kinase. Treatment of cells with the alpha(7) nicotinic acetylcholine receptor inhibitor alpha-bungarotoxin can block nicotine-induced calpain phosphorylation with suppression of calpain activity, wound healing, cell migration, and invasion, indicating that nicotine-induced calpain phosphorylation occurs, at least in part, through a signaling pathway involving the upstream alpha(7) nicotinic acetylcholine receptor. Intriguingly, depletion of PKC iota by RNA interference suppresses nicotine-induced calpain phosphorylation, calpain activity, cell migration, and invasion, indicating that PKC iota is a necessary component in nicotine-mediated cell motility signaling. Importantly, nicotine potently induces secretion of mu- and m-calpains from lung cancer cells into culture medium, which may have potential to cleave substrates in the extracellular matrix. These findings reveal a novel role for PKC iota as a nicotine-activated, physiological calpain kinase that directly phosphorylates and activates calpains, leading to enhanced migration and invasion of human lung cancer cells.