Bacterial enterotoxins are associated with resistance to colon cancer
Bacterial enterotoxins are associated with resistance to colon cancer
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DOI：
10.1073/pnas.0434905100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
Waldman, SA
中科院分区：
文献类型：
--
作者：
Pitari, GM;Zingman, LV;Waldman, SA
在工业化国家，有50万患者患有结肠直肠癌，但在不发达国家，这种疾病的发病率很低。这种地理上的不平衡表明，环境因素对地方性人群对肠道肿瘤的抵抗力起了作用。这些结肠癌幸免地区的一个共同流行病学特征是与腹泻疾病相关的产肠毒素细菌的流行。在这里，一种细菌热稳定的肠毒素被证明可以通过guanyyl环化酶c介导的信号级联抑制结肠癌细胞的增殖。热稳定的肠毒素通过增加细胞内cGMP来抑制增殖，这种作用被细胞渗透的类似物8-br-cGMP所模仿。肠毒素和8-br-cGMP的抗增殖作用被l -顺式地尔硫卓逆转，一种环核苷酸门控通道抑制剂，以及通过去除细胞外Ca2+，或螯合细胞内Ca2+。事实上，肠毒素和8-br-cGMP都诱导了l -顺式地尔硫卓敏感的传导，促进了Ca2+内流，抑制了结肠癌细胞的DNA合成。细菌肠毒素诱导这种以前未被认识到的抗增殖信号通路可能有助于地方性人群对肠道肿瘤的抵抗，并为原发性和转移性结直肠癌的靶向预防和治疗提供了一个范例。
One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in underdeveloped countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca2+, or chelation of intracellular Ca2+. In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca2+ influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.