The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine activates the extracellular signal-regulated kinase mitogen-activated protein kinase pathway
The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine activates the extracellular signal-regulated kinase mitogen-activated protein kinase pathway
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DOI：
10.1158/0008-5472.can-07-2821
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Gooderham, Nigel J.
中科院分区：
文献类型：
--
作者：
Creton, Stuart K.;Zhu, Huijun;Gooderham, Nigel J.
在肉类的烹饪过程中，会形成致突变和致癌的杂环胺，其中最丰富的是2-氨基-1-甲基-6-苯基咪唑[4-5-B]吡啶（PhIP），可诱导大鼠前列腺、结肠和乳腺肿瘤。食用熟肉的人每天都会接触到PhIP，但很少有研究评估PhIP在饮食相关浓度下的影响。除了其遗传毒性特性外，最近的研究表明，PhIP可以激活雌激素受体介导的信号通路，其剂量与食用熟肉后体内可能存在的剂量相似。在本研究中，我们研究了这样的剂量的PhIP是否可以影响雌激素受体的非依赖性信号转导通过丝裂原活化蛋白激酶（MAPK）细胞外信号相关激酶（ERK）途径，影响人乳腺上皮细胞系MCF 10A和前列腺癌细胞系PC-3的增殖和迁移。在对MCF 10A细胞具有增殖作用的剂量（10（-11）-10（-7）mol/L）下，PhIP诱导MAPK/ERK激酶1/2和ERK磷酸化的快速、瞬时增加。抑制这一通路可显著降低PhIP诱导的MCF-10A细胞增殖和PC-3细胞迁移。这里提供的数据表明，接近人类饮食暴露的PhIP水平刺激细胞信号传导途径，并导致生长和迁移增加，这些过程与肿瘤疾病的促进和进展有关。这些发现提供了强有力的证据，证明PhIP作为肿瘤引发剂和促进剂，并且饮食暴露于这种化合物可能导致人类致癌。
During the cooking of meat, mutagenic and carcinogenic heterocyclic amines are formed, the most abundant of which, 2-amino-1-methyl-6-phenylimidazo[4-5-b]pyridine (PhIP), induces tumors of the prostate, colon, and mammary gland in rats. Humans consuming cooked meat are exposed to PhIP on a daily basis, yet few studies have assessed the effects of PhIP at dietary relevant concentrations. In addition to its genotoxic properties, recent studies have shown that PhIP can activate estrogen receptor-mediated signaling pathways at doses that are similar to those that may be present in the body following consumption of a cooked meat meal. In the present study, we examined whether such doses of PhIP can affect estrogen receptor-independent signal transduction via the mitogen-activated protein kinase (MAPK) extracellular signal-related kinase (ERK) pathway to influence proliferation and migration in the human mammary epithelial cell line MCF10A and the prostate cancer cell line PC-3. At doses shown to have a proliferative effect on MCF10A cells (10(-11)-10(-7) mol/L), PhIP induced a rapid, transient increase in phosphorylation of both MAPK/ERK kinase 1/2 and ERKs. Inhibition of this pathway significantly reduced the PhIP-induced proliferation of MCF10A cells and the migration of PC-3 cells. The data presented here show that levels of PhIP that approximate to human dietary exposure stimulate cellular signaling pathways and result in increased growth and migration, processes linked to the promotion and progression of neoplastic disease. These findings provide strong evidence that PhIP acts as a tumor initiator and promoter and that dietary exposure to this compound could contribute to carcinogenesis in humans.