Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors
Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors
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DOI：
10.1016/j.bcp.2005.07.023
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发表时间：
2005-10-01
影响因子：
5.8
通讯作者：
Raufman, JP
中科院分区：
文献类型：
--
作者：
Cheng, KR;Raufman, JP
虽然流行病学研究表明粪便胆汁酸升高与结直肠癌的发生有关，但胆汁酸增殖作用的细胞机制尚不清楚。来自其他实验室的研究表明，胆汁酸对细胞培养株具有自相矛盾的促凋亡作用。我们以前的研究表明，胆碱能激动剂诱导表达M-3 M受体(M3R)的结肠癌细胞的增殖是由表皮生长因子受体(EGFR)的反式激活介导的，胆汁酸刺激表达M3R的结肠癌细胞的增殖。在本研究中，我们研究了胆汁酸对高表达M3R和EGFR的人结肠癌细胞系(H508细胞)细胞信号和增殖的影响。胆石酸和脱氧胆酸的牛磺酸和甘氨酸结合物可促进p44/42MAP信号转导通路的可逆激活和H508细胞的增殖。胆汁酸不能刺激表达EGFR但不表达M受体的SNU-C4结肠癌细胞的增殖。M受体反向激动剂阿托品可阻断胆汁酸诱导的H508细胞增殖。在刺激细胞增殖的浓度下，结合胆汁酸不能激活caspase-3，caspase-3是细胞凋亡的关键媒介。结合胆汁酸刺激EGFR Tyr992的磷酸化，从而在其增殖作用的细胞机制中暗示EGFR的反式激活。通过观察EGFR激活的抑制剂和针对EGFR配体结合域的抗体阻止胆汁酸的信号和增殖作用，证实了这一点。总之，这些结果表明，在该结肠癌细胞系中，胆汁酸诱导的结肠癌细胞增殖是M3R依赖的，并由EGFR的反式激活介导。(C)2005 Elsevier Inc.保留所有权利。
Although epidemiological studies indicate an association between elevations in fecal bile acids and the development of colorectal cancer, the cellular mechanism for the proliferative actions of bile acids is not clear. Studies from other laboratories indicate a paradoxical pro-apoptotic action of bile acids on cell culture lines. Our previous studies indicate that cholinergic agonist-induced proliferation of colon cancer cells that express M-3 muscarinic receptors (M3R) is mediated by transactivation of the epidermal growth factor receptor (EGFR) and that bile acids stimulate proliferation of colon cancer cells that express M3R. In the present study, we investigated the effects of bile acids on cell signaling and proliferation of a human colon cancer cell line (H508 cells) that abundantly expresses M3R and EGFR. Treatment with taurine and glycine conjugates of lithocholic and deoxycholic acids stimulated reversible activation of the p44/42 MAP kinase signaling cascade and proliferation of H508 cells. Bile acids did not stimulate proliferation of SNU-C4 colon cancer cells that express EGFR but not muscarinic receptors. Atropine, a muscarinic receptor inverse agonist, blocked bile acid-induced H508 cell proliferation. At concentrations that stimulate cell proliferation, conjugated bile acids did not activate caspase-3, a key mediator of apoptosis. Conjugated bile acids stimulated phosphorylation of EGFR Tyr992, thereby implicating EGFR transactivation in the cellular mechanism underlying their proliferative actions. This was confirmed by observing that inhibitors of EGFR activation and antibodies to the ligand-binding domain of EGFR blocked both the signaling and proliferative actions of bile acids. Collectively, these results suggest that in this colon cancer cell line, bile acid-induced colon cancer cell proliferation is M3R-dependent and is mediated by transactivation of EGFR. (c) 2005 Elsevier Inc. All rights reserved.