Tannheimer S L, Ethier S P, Caldwell K K, Burchiel S W
Toxicology Program, University of New Mexico College of Pharmacy, Albuquerque 87131, USA.
Carcinogenesis. 1998 Jul;19(7):1291-7. doi: 10.1093/carcin/19.7.1291.
Previous studies in this laboratory have shown that polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (BaP), and certain halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), modulate receptor signaling pathways in human lymphoid and non-lymphoid cells. We have recently demonstrated that BaP produces a weak mitogenic signal in human mammary epithelial cells, perhaps by mimicking growth factor signaling pathways. In the present studies we found that BaP and TCDD activated insulin-like growth factor (IGF-I) signaling pathways under insulin-deficient conditions. The effects of BaP and TCDD were evaluated in the human MCF-10A mammary epithelial cell line grown under epidermal growth factor- and insulin-dependent conditions. BaP (0.3 microM) and TCDD (30 nM) were found to restore a moderate insulin-like signal in MCF-10A cells grown in the absence of added insulin. TCDD was more potent and produced better activation of cell growth than did BaP. Both TCDD and BaP appeared to mimic signaling through the IGF-I receptor (IGF-IR), as evidenced by increased tyrosine phosphophorylation of IGF-IRbeta, IRS-1 and Shc. In addition, both BaP and TCDD significantly increased the activity of phosphatidylinositol 3-kinase (PI3K). The PI3K inhibitor LY294002 was found to inhibit the growth-promoting effects of TCDD seen under insulin-deficient conditions. The results of these studies show that under certain conditions BaP and TCDD can mimic growth factor signaling pathways in human mammary epithelial cells, demonstrating that environmentally prevalent carcinogenic compounds may alter cell growth in human mammary epithelial cells via mimicry of growth factor receptor signaling pathways.
本实验室之前的研究表明，多环芳烃，如苯并[a]芘（BaP），以及某些卤代芳烃，如2,3,7,8-四氯二苯并对二恶英（TCDD），可调节人类淋巴细胞和非淋巴细胞中的受体信号通路。我们最近证明，BaP可能通过模拟生长因子信号通路，在人乳腺上皮细胞中产生微弱的促有丝分裂信号。在本研究中，我们发现BaP和TCDD在胰岛素缺乏的条件下激活胰岛素样生长因子（IGF-I）信号通路。在表皮生长因子和胰岛素依赖条件下培养的人MCF-10A乳腺上皮细胞系中评估了BaP和TCDD的作用。发现BaP（0.3 microM）和TCDD（30 nM）可在未添加胰岛素的情况下培养的MCF-10A细胞中恢复适度的胰岛素样信号。TCDD比BaP更有效，对细胞生长的激活作用更好。TCDD和BaP似乎都模拟了通过IGF-I受体（IGF-IR）的信号传导，IGF-IRβ、IRS-1和Shc的酪氨酸磷酸化增加证明了这一点。此外，BaP和TCDD均显著增加了磷脂酰肌醇3激酶（PI3K）的活性。发现PI3K抑制剂LY294002可抑制在胰岛素缺乏条件下观察到TCDD的促生长作用。这些研究结果表明，在某些条件下，BaP和TCDD可模拟人乳腺上皮细胞中的生长因子信号通路，表明环境中普遍存在的致癌化合物可能通过模拟生长因子受体信号通路改变人乳腺上皮细胞的生长。
