Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma.
Nicotine induces inhibitor of differentiation-1 in a Src-dependent pathway promoting metastasis and chemoresistance in pancreatic adenocarcinoma.
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DOI：
10.1593/neo.121044
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发表时间：
2012-12
期刊：
影响因子：
4.8
通讯作者：
J. Trevino;S. Pillai;Sateesh S. Kunigal;S. Singh;W. Fulp;B. Centeno;S. Chellappan
中科院分区：
文献类型：
--
作者：
J. Trevino;S. Pillai;Sateesh S. Kunigal;S. Singh;W. Fulp;B. Centeno;S. Chellappan
吸烟是胰腺癌的一个重要危险因素，但烟草烟雾成分促进这些癌症生长和进展的分子机制尚未完全了解。虽然烟草烟雾中的成瘾成分尼古丁不是致癌物质，但已显示它以受体依赖的方式促进非小细胞肺癌和胰腺癌的生长。在这里，我们表明，刺激胰腺癌细胞与尼古丁浓度范围内的人类接触的结果激活Src激酶，这有利于诱导分化抑制因子-1（Id 1）转录因子。Id 1的耗尽阻止了尼古丁介导的胰腺癌细胞增殖和侵袭的诱导，表明它是尼古丁功能的主要介质。尼古丁可以促进原位植入SCID小鼠的胰腺癌的生长和转移;此外，稳定表达Id 1短发夹RNA的细胞对尼古丁没有反应，也没有生长或转移。尼古丁也可以赋予抵抗吉西他滨诱导的胰腺癌细胞凋亡在体外和Src或Id 1的耗尽呈现细胞对吉西他滨敏感。此外，尼古丁可有效抑制吉西他滨对异种移植到小鼠中的胰腺肿瘤的化疗作用。对切除的胰腺癌标本的临床分析表明，Id 1表达与磷酸化Src、肿瘤分级/分化和患者总体生存率恶化之间存在统计学显著相关性。这些结果表明，暴露于烟草烟雾成分可能会促进胰腺癌的进展，转移和耐药性，并突出了Id 1在这些过程中的作用。
Smoking is a significant risk factor for pancreatic cancer, but the molecular mechanisms by which tobacco smoke components promote the growth and progression of these cancers are not fully understood. While nicotine, the addictive component of tobacco smoke, is not a carcinogen, it has been shown to promote the growth of non-small cell lung and pancreatic cancers in a receptor-dependent fashion. Here, we show that stimulation of pancreatic cancer cells with nicotine concentrations that are within the range of human exposure results in activation of Src kinase, which facilitated the induction of the inhibitor of differentiation-1 (Id1) transcription factor. Depletion of Id1 prevented nicotine-mediated induction of proliferation and invasion of pancreatic cancer cells, indicating that it is a major mediator of nicotine function. Nicotine could promote the growth and metastasis of pancreatic cancers orthotopically implanted into SCID mice; in addition, cells stably expressing a short hairpin RNA for Id1 did not grow or metastasize in response to nicotine. Nicotine could also confer resistance to apoptosis induced by gemcitabine in pancreatic cancer cells in vitro and depletion of Src or Id1 rendered the cells sensitive to gemcitabine. Further, nicotine could effectively inhibit the chemotherapeutic effects of gemcitabine on pancreatic tumors xenografted into mice. Clinical analyses of resected pancreatic cancer specimens demonstrated a statistically significant correlation between Id1 expression and phospho-Src, tumor grade/differentiation, and worsening overall patient survival. These results demonstrate that exposure to tobacco smoke components might promote pancreatic cancer progression, metastasis, and chemoresistance and highlight the role of Id1 in these processes.