Weddle D L, Tithoff P, Williams M, Schuller H M
Carcinogenesis and Developmental Therapeutics Program, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
Carcinogenesis. 2001 Mar;22(3):473-9. doi: 10.1093/carcin/22.3.473.
Exocrine ductal carcinoma of the pancreas has been associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation, our data show high basal levels of AA release in two human cell lines derived from exocrine ductal pancreatic carcinomas. Both cell lines expressed m-RNA for beta2-adrenergic receptors and beta1-adrenergic receptors. Radio-receptor assays showed that beta2-adrenergic receptors predominated over beta1-adrenergic receptors. beta2-Adrenergic antagonist ICI118,551 significantly reduced basal AA release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly stimulated by NNK when cells were maintained in complete medium and this response was inhibited by the beta-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886. Panc-1 cells were more sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our findings are in accord with a recent report which has identified NNK as a beta-adrenergic agonist and suggest beta-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer intervention strategies.
胰腺外分泌导管癌与吸烟有关，烟草特异性亚硝胺4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)可在实验啮齿动物中引发这种癌症。目前关于这种恶性肿瘤生长调节的知识极为有限。最近的研究表明，环氧化酶2(COX 2)和5-脂氧合酶(5-脂氧)在外分泌性胰腺癌中过表达，提示花生四烯酸(AA)级联反应在这种癌症类型的调节中可能发挥作用。支持这一解释的是，我们的数据显示，源自胰腺外分泌导管癌的两个人类细胞系中AA释放的基础水平较高。两个细胞系均表达β2-肾上腺素能受体和β1-肾上腺素能受体的信使核糖核酸。放射受体分析表明，β2-肾上腺素能受体占主导地位，超过β1-肾上腺素能受体。当细胞在完全培养基中培养时，β2-肾上腺素能拮抗剂ICI118,551显著降低基础AA释放和DNA合成。当细胞在完全培养基中培养时，具有ki-ras基因第12密码子激活点突变的细胞系(Panc-1)的DNA合成受到NNK的显著刺激，而这种反应受到β阻滞剂ICI118,551、COX抑制剂阿司匹林或5-脂氧抑制剂MK-886的抑制。没有ras突变的细胞系(BXPC-3)在完全培养基中对NNK没有显著反应。当在无血清培养基中进行测定时，两个细胞系对NNK的反应均表现为DNA合成增加，这种效应受到β2阻滞剂、阿司匹林或MK-886的抑制。与BXPC-3细胞相比，Panc-1细胞对NNK的刺激作用更敏感，对抑制剂的反应更小。我们的发现与最近一份将NNK鉴定为β-肾上腺素能激动剂的报告一致，并提示胰腺癌中β-肾上腺素能、AA依赖性调节途径是癌症干预策略的新靶点。
