Cadmium and Cancer
Cadmium and Cancer
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DOI：
10.1007/978-94-007-5179-8_15
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Hartwig, Andrea
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文献类型：
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作者：
Hartwig, Andrea
镉是公认的人类和动物致癌物。大多数证据表明，职业暴露后肺癌风险升高；然而，镉暴露与肾、乳腺和前列腺等其他部位的肿瘤之间的联系也可能相关。此外，癌症风险的增加可能不仅限于相对较高的职业接触，也可能通过环境接触发生，例如在靠近锌冶炼厂的地区。潜在的机制仍然是多方面研究活动的问题。虽然与DNA的直接相互作用似乎不太重要，但在不同的实验系统中检测到活性氧（ROS）水平升高，可能是由于解毒酶的失活。此外，对参与细胞对DNA损伤反应的蛋白质的干扰，细胞生长的失调以及对凋亡的抵抗似乎与镉诱导的致癌性有关。在这种情况下，镉已被证明会干扰核苷酸切除修复、碱基切除修复和错配修复。特别敏感的靶标似乎是具有锌结合结构的蛋白质，存在于DNA修复蛋白中，如XPA， PARP-1以及肿瘤抑制蛋白p53。这些相互作用是由于锌的位移，还是由于在实际暴露条件下与锌络合或其他关键位置的硫基的反应，仍有待阐明。进一步的潜在机制与干扰细胞氧化还原调节有关，要么通过增强ROS的产生，要么通过与参与信号通路调节的巯基反应。特别是这些多种机制的结合可能导致镉适应细胞中明显的高度基因组不稳定性，这不仅与肿瘤的发生有关，而且与肿瘤发展的后期步骤有关。
Cadmium is an established human and animal carcinogen. Most evidence is available for elevated risk for lung cancer after occupational exposure; however, associations between cadmium exposure and tumors at other locations including kidney, breast, and prostate may be relevant as well. Furthermore, enhanced cancer risk may not be restricted to comparatively high occupational exposure, but may also occur via environmental exposure, for example in areas in close proximity to zinc smelters. The underlying mechanisms are still a matter of manifold research activities. While direct interactions with DNA appear to be of minor importance, elevated levels of reactive oxygen species (ROS) have been detected in diverse experimental systems, presumably due to an inactivation of detoxifying enzymes. Also, the interference with proteins involved in the cellular response to DNA damage, the deregulation of cell growth as well as resistance to apoptosis appears to be involved in cadmium-induced carcinogenicity. Within this context, cadmium has been shown to disturb nucleotide excision repair, base excision repair, and mismatch repair. Particularly sensitive targets appear to be proteins with zinc-binding structures, present in DNA repair proteins such as XPA, PARP-1 as well as in the tumor suppressor protein p53. Whether or not these interactions are due to displacement of zinc or due to reactions with thiol groups involved in zinc complexation or in other critical positions under realistic exposure conditions remains to be elucidated. Further potential mechanisms relate to the interference with cellular redox regulation, either by enhanced generation of ROS or by reaction with thiol groups involved in the regulation of signaling pathways. Particularly the combination of these multiple mechanisms may give rise to a high degree of genomic instability evident in cadmium-adapted cells, relevant not only for tumor initiation, but also for later steps in tumor development.