Arsenic carcinogenicity: Metabolic disruption leads to loss of PTEN function

砷致癌性：代谢紊乱导致 PTEN 功能丧失

• 批准号: 8681231
• 负责人: WALTER T KLIMECKI
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-19 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681231
• 关键词: Aerobic; Affect; Agar; Anabolism; Arsenic; Arsenites; Bladder; Cancer Etiology; Carbohydrates; Cell Culture Techniques; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Metabolic Process; Cellular biology; Chemicals; Chronic; Complement; Culture Media; Cultured Cells; Data; Diploidy; Effector Cell; Elements; Energy Metabolism; Environmental Exposure; Epidemiology; Epigenetic Process; Epithelial Cells; Etiology; Event; Exposure to; Foundations; Genes; Genetic; Glycolysis; Growth; Homologous Gene; Human; In Vitro; Incidence; Lung; Malignant - descriptor; Malignant Neoplasms; Measurement; Mediator of activation protein; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular Biology; Monitor; Multienzyme Complexes; NADH; Non-Malignant; Oxidative Phosphorylation; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Ploidies; Poisoning; Production; Proteins; Protocols documentation; Reaction; Recording of previous events; Reporting; Seminal; Signal Transduction; Skin; Techniques; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Tumor Suppressor Genes; Tumor Suppressor Proteins; Warburg Effect; Work; aerobic glycolysis; anticancer research; carcinogenesis; carcinogenicity; cofactor; design; environmental carcinogenesis; functional loss; human disease; indexing; loss of function; member; novel; prevent; public health relevance; tensin; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Human arsenic exposure has been referred to as the worst environmental poisoning in modern human history. Arsenic toxicity in exposed humans causes cancer in diverse target tissues, including lung, bladder and skin. Despite incontrovertible epidemiology that repeatable confirms arsenic carcinogenicity, no definitive mechanism explaining the carcinogenic action of arsenic exists. The phosphatase and tensin homologue (PTEN) gene is a tumor suppressor gene that holds a unique place in human cancer research, in that it is arguably the only tumor suppressor gene that is commonly involved through loss of function in both familial and sporadic cancers. The principal tumor-suppressive mechanism of PTEN is through it inactivation of the Akt pathway, a central effector of cell survival and proliferation. Akt activation is a frequently reported consequence of chronic arsenic exposure in vitro, including cell culture models of arsenic-induced malignant transformation. This project seeks to test a novel mechanism by which arsenic exposure could inactivate PTEN, leading to loss of its tumor-suppressive function, leading to Akt activation and arsenic-induced carcinogenesis. Using a cell culture model amenable to in vitro studies of malignant transformation, our preliminary data establish that a general effect of inorganic trivalent arsenic (arsenite) exposure is the disruption of cellular metabolism, including the induction of aerobic glycolysis and elevation of intracellular NADH level. This is intriguing because PTEN activity has been demonstrated to be inhibited by elevated NADH. We hypothesize that an important mechanism of arsenic's carcinogenic action is its ability to disturb fundamental cell metabolism, leading to elevated NADH levels, and the functional loss of the tumor suppressor, PTEN. Two specific aims will test this hypothesis. Aim 1 will define the temporal relationship and associations between PTEN activity, Akt activation, and key phenotypes associated with the acquisition of malignancy in BEAS-2B cells chronically exposed to a non-cytotoxic, environmentally relevant concentration of arsenite. Aim 2 is designed to incorporate data collected in Aim 1 to affect sustained, experimentally modulated, increased and decreased NADH level in derived BEAS-2B cell lines. These BEAS-2B cell lines will be subjected to the malignant transformation protocol used in Aim 1 (1 um arsenite for approximately 17 weeks). Our hypothesis predicts that upward or downward modulation of NADH level will result in enhanced or diminished malignant transformation, respectively. This R03 project proposes an initial test of a novel mechanism involving metabolic control of cell signaling in environmental carcinogenesis.

描述（由申请人提供）：人类砷暴露被称为现代人类历史上最严重的环境中毒。暴露于砷的人体中的砷毒性会导致多种靶组织发生癌症，包括肺、膀胱和皮肤。尽管无可争议的流行病学可重复证实砷的致癌性，但尚不存在解释砷致癌作用的明确机制。磷酸酶和张力蛋白同源物 (PTEN) 基因是一种肿瘤抑制基因，在人类癌症研究中占有独特的地位，因为它可以说是唯一一个在家族性和散发性癌症中通常与功能丧失有关的肿瘤抑制基因。 PTEN 的主要肿瘤抑制机制是通过其灭活 Akt 通路（细胞存活和增殖的核心效应器）。 Akt 激活是体外慢性砷暴露的常见结果，包括砷诱导恶性转化的细胞培养模型。该项目旨在测试一种新机制，砷暴露可使 PTEN 失活，导致其肿瘤抑制功能丧失，从而导致 Akt 激活和砷诱发的致癌作用。使用适合体外恶性转化研究的细胞培养模型，我们的初步数据表明，无机三价砷的一般作用 （亚砷酸盐）暴露会破坏细胞代谢，包括诱导有氧糖酵解和细胞内 NADH 水平升高。这很有趣，因为 PTEN 活性已被证明会被升高的 NADH 抑制。我们推测砷致癌作用的一个重要机制是其扰乱基本细胞代谢的能力，导致 NADH 水平升高以及肿瘤抑制因子 PTEN 的功能丧失。有两个具体目标将检验这一假设。目标 1 将定义 PTEN 活性、Akt 激活以及与长期暴露于非细胞毒性、环境相关浓度的亚砷酸盐的 BEAS-2B 细胞中获得恶性肿瘤相关的关键表型之间的时间关系和关联。目标 2 旨在整合目标 1 中收集的数据，以影响衍生的 BEAS-2B 细胞系中持续的、实验调节的、增加和减少的 NADH 水平。这些 BEAS-2B 细胞系将​​接受目标 1 中使用的恶性转化方案（1 um 亚砷酸盐约 17 周）。我们的假设预测 NADH 水平的向上或向下调节将分别导致恶性转化的增强或减弱。该 R03 项目提出了对一种新机制的初步测试，该机制涉及环境致癌过程中细胞信号传导的代谢控制。