MECHANISMS OF INORGANIC CARCINOGENESIS

无机致癌机制

• 批准号: 6289111
• 负责人: MICHAEL WAALKES
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289111
• 关键词: DNA damage; arsenic; cadmium; cancer risk; carcinogenesis inhibitor; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; environment related neoplasm /cancer; gene induction /repression; hazardous substances; kidney neoplasms; laboratory mouse; laboratory rat; lead; liver neoplasms; lung neoplasms; metallothionein; prostate neoplasms; protooncogene

Many inorganics are carcinogenic in exposed human populations while others are suspected of such activity. As carcinogens, inorganics are very hazardous because they are ubiquitous, non-biodegradable, bioaccumulated, and mimic essential elements in biological systems. Human exposure to inorganics is inevitable and defining their mechanisms of action is critical in assessing the nature and extent of the human health hazard posed by such exposure. Arsenic, cadmium and lead are distinct among metal carcinogens because they do not undergo spontaneous redox reactions and the creation of electrophilic species that directly attack DNA is unlikely. Thus, we are actively considering alternative, epigenetic mechanisms for these metals. Indirect mechanisms by which metals induce aberrant gene expression and malignant transformation under study include interactions with regulatory proteins, altered DNA methylation status, interactions with DNA binding proteins or alterations in receptor mediated processes. Basic aspects of site specific sensitivity are also being explored, and with cadmium poor responsiveness of the metallothionein (MT) gene often dictates susceptibility. Site specificity determinants for arsenic are as yet unknown but may be linked to the tissues that most actively methylate this metalloid. We find that during arsenic-induced malignant transformation, DNA becomes hypomethylated, which, in turn, facilitates aberrant oncogene activation, including activation of c-myc and c-met. This is likely due to the consumption of cellular methyl groups in arsenic metabolism which reduces their availability for DNA methyltransferases and consequently reduces activity. On the other hand, transformation by cadmium in vitro is associated with genomic DNA hypermethylation, which can be linked to tumor suppressor gene inactivation. We also find that cadmium can block apoptosis subsequent to DNA damage from direct acting genotoxins, which allows a greater portion of genetically damaged cells to escape normal cell check points and could be an important factor in an epigenetic mechanism of carcinogenesis. Cadmium is also associated with activation of proto- oncogenes in human prostate epithelial cells. Cadmium can also be anti- apoptotic in these cells as well. In addition, recent work from our Section in whole animals indicates that cadmium can induce prostate tumors in the dorsolateral lobe of the rat, a lobe considered analogous to the human organ. Prostate cancer is an important and often deadly human malignancy that has been linked with human exposure to cadmium. - Animal models, Chemical carcinogenesis, Proto-oncogenes, Transformation, Metalloprotein, Apoptosis,

许多无机物在暴露的人群中具有致癌性，而其他无机物则被怀疑具有这种活性。作为致癌物，无机物非常危险，因为它们无处不在、不可生物降解、可生物蓄积并模仿生物系统中的基本元素。人类接触无机物是不可避免的，确定其作用机制对于评估此类接触对人类健康危害的性质和程度至关重要。砷、镉和铅是不同的金属致癌物，因为它们不会发生自发的氧化还原反应，并且不太可能产生直接攻击 DNA 的亲电子物质。因此，我们正在积极考虑这些金属的替代表观遗传机制。正在研究的金属诱导异常基因表达和恶性转化的间接机制包括与调节蛋白的相互作用、改变的DNA甲基化状态、与DNA结合蛋白的相互作用或受体介导过程的改变。位点特异性敏感性的基本方面也在探索中，金属硫蛋白（MT）基因对镉的不良反应性通常决定了敏感性。砷的位点特异性决定因素尚不清楚，但可能与最活跃甲基化该类金属的组织有关。我们发现，在砷诱导的恶性转化过程中，DNA 变得低甲基化，这反过来又促进了癌基因的异常激活，包括 c-myc 和 c-met 的激活。这可能是由于砷代谢中细胞甲基的消耗减少了 DNA 甲基转移酶的可用性，从而降低了活性。另一方面，体外镉的转化与基因组 DNA 高甲基化有关，这可能与抑癌基因失活有关。我们还发现，镉可以阻止直接作用的基因毒素造成的 DNA 损伤后的细胞凋亡，从而使大部分基因受损的细胞逃脱正常细胞检查点，并且可能是致癌的表观遗传机制中的一个重要因素。镉还与人前列腺上皮细胞中原癌基因的激活有关。镉也可以在这些细胞中具有抗凋亡作用。此外，我们部门最近在整个动物中的研究表明，镉可以在大鼠的背外侧叶中诱发前列腺肿瘤，该叶被认为与人体器官类似。前列腺癌是一种重要且往往致命的人类恶性肿瘤，与人类接触镉有关。 - 动物模型、化学致癌、原癌基因、转化、金属蛋白、细胞凋亡、