Askari Minoo D F, Tsao Ming-Sound, Cekanova Maria, Schuller Hildegard M
Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
Pancreas. 2006 Jul;33(1):53-62. doi: 10.1097/01.mpa.0000226883.55828.e9.
Smoking is a well-documented risk factor for pancreatic cancer. The tobacco-specific nitrosamine, NNK (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone), significantly induces pancreatic ductal adenocarcinomas in laboratory rodents. Recent observations suggest that ethanol enhances the tumorigenic effects of smoking. Ethanol consumption is associated with the development of chronic pancreatitis, also considered a predisposing factor for pancreatic ductal adenocarcinoma. Because the precise role of ethanol in pancreatic carcinogenesis is not known, this study sought to elucidate the cumulative effects of ethanol and NNK on particular signal transduction pathways that might play a role in cell proliferation in immortalized human pancreatic duct epithelial cells.
The HPDE6-c7 cells are developed from pancreatic duct epithelial cells, which are the putative cells of origin of pancreatic ductal adenocarcinoma. Cell proliferation assays, Western blot, and cyclic adenosine monophosphate assays were used to demonstrate the effects of ethanol and NNK treatments on these cells.
Ethanol cotreatments enhanced the NNK-induced proliferation of these cells. This response was inhibited by the adenylyl cyclase, protein kinase A, mitogen-activated protein kinase (p42/p44), and epidermal growth factor receptor-specific tyrosine kinase inhibitors. Cotreatments of NNK and ethanol also increased cyclic adenosine monophosphate accumulation, cAMP response element-binding family of proteins and mitogen-activated protein kinase phosphorylation, and protein kinase A activation.
These findings suggest a potential role for these pathways contributing to the development of smoking- and alcohol-related pancreatic carcinogenesis.
吸烟是胰腺癌一个有充分文献记载的风险因素。烟草特异性亚硝胺NNK（4-[甲基亚硝基氨基]-1-[3-吡啶基]-1-丁酮）在实验啮齿动物中能显著诱发胰腺导管腺癌。最近的观察表明，乙醇会增强吸烟的致癌作用。乙醇消费与慢性胰腺炎的发生有关，慢性胰腺炎也被认为是胰腺导管腺癌的一个诱发因素。由于乙醇在胰腺癌发生过程中的确切作用尚不清楚，本研究旨在阐明乙醇和NNK对特定信号转导途径的累积效应，这些途径可能在永生化人胰腺导管上皮细胞的细胞增殖中发挥作用。
HPDE6-c7细胞由胰腺导管上皮细胞发育而来，胰腺导管上皮细胞被认为是胰腺导管腺癌的起源细胞。采用细胞增殖试验、蛋白质印迹法和环磷酸腺苷试验来证明乙醇和NNK处理对这些细胞的影响。
乙醇联合处理增强了NNK诱导的这些细胞的增殖。腺苷酸环化酶、蛋白激酶A、丝裂原活化蛋白激酶（p42/p44）和表皮生长因子受体特异性酪氨酸激酶抑制剂可抑制这种反应。NNK与乙醇的联合处理还增加了环磷酸腺苷的积累、环磷酸腺苷反应元件结合蛋白家族和丝裂原活化蛋白激酶的磷酸化以及蛋白激酶A的激活。
这些发现表明这些信号转导途径在吸烟和酒精相关的胰腺癌发生发展中可能发挥作用。
