Mechanisms of arsenic-induced carcinogenesis

砷致癌机制

• 批准号: 9280784
• 负责人: KESHAV K SINGH
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280784
• 关键词: Address; Affect; Anchorage-Independent Growth; Applications Grants; Arsenic; Binding; Biological Assay; Breast; Breast Cancer Cell; Breast Epithelial Cells; Carcinogens; Catalysis; Cell Death; Cell Proliferation; Cell model; Cell physiology; Chemicals; Chemopreventive Agent; Chromosomes; Complex; Concha; Cutaneous Fibrous Histiocytoma; Development; Dose; Endocrine Disruptors; Estradiol; Estrogens; Exposure to; Female; Functional disorder; Future; Gene Expression; Genes; Goals; Growth; Health; Hormones; Human; Induced Mutation; Interferons; Laboratories; Laboratory Animals; Ligands; Link; Long-Term Effects; Malignant Neoplasms; Mammary Gland Parenchyma; Measures; Military Personnel; Mission; Mitochondria; Mitochondrial DNA; New Agents; Oxidative Phosphorylation; Play; Population Study; Process; Production; Reactive Oxygen Species; Reporting; Research; Resistance; Retinoids; Risk; Role; Therapeutic Agents; Tumorigenicity; Veterans; Woman; Wound Healing; arsenic-induced carcinogenesis; base; cell growth; cell transformation; complex IV; exposed human population; insight; malignant breast neoplasm; matrigel; mitochondrial DNA mutation; model development; mortality; prevent; public health relevance; respiratory; tumor; tumorigenic

DESCRIPTION (provided by applicant): Since a significant number of women serve in the military an increasing number of female veterans are impacted by breast cancer. The long-term goal of this research is to develop chemo-preventive and therapeutic agents against breast cancer to reduce the health burden in female military personnel. The current goal of this research is to identify mechanisms involved in the development of arsenic-induced breast cancer. To replicate normal field exposure conditions, we exposed breast epithelial cells to low dose of arsenic for several months. We discovered that a five month continuous exposure of breast epithelial cells to arsenic results in increased cell proliferation, increased wound healing, increased anchorage independent growth, as well as increased matrigel invasion. These studies suggest arsenic induces tumorigenic transformation of breast epithelial cells. Our preliminary studies revealed that mitochondria are important targets of arsenic induced transformation. Mitochondria control cell growth and cell death. Mitochondria perform other cellular functions including ATP production via mitochondrial oxidative phosphorylation (mtOXPHOS). We discovered that exposure to arsenic induces selective subgenomic amplification of chromosome 5p which contains many genes involved in mitochondrial function. Consistent with this finding arsenic-transformed cells show 1) increased Complex I and IV activities; 2) an increased expression of Complex I regulatory subunits NDUFA13 or GRIM19 (gene associated with retinoid interferon induced mortality) and non-regulatory NDUFB8 comprising the mtOXPHOS; and 3) increased expression of COXII subunit comprising complex IV. Furthermore our study suggest that arsenic-treatment did not 1) induce changes in Complex II and III activities and 2) alter the expression of arsenic-transporters. However, arsenic-transformed cells produce an increased level of reactive oxygen species. We hypothesize that arsenic disrupts mtOXPHOS function which contributes to tumorigenic transformation of breast epithelial cells. To address the proposed hypothesis, we plan to: Aim 1: Determine the spectrum of arsenic-induced mtOXPHOS dysfunction during progression (1, 2, 3, 4 months) to tumorigenic transformation (5 months) of mammary epithelial cells. Aim 2: Determine arsenic-induced changes affecting subunit gene expression, composition and organization of mtOXPHOS super-complexes during the progression and tumorigenic transformation of mammary epithelial cells. Aim 3: Determine a role for a regulatory and a non-regulatory subunit of mtOXPHOS Complex I in resistance to arsenic-induced cell death and tumor development. NDUFA13/GRIM19 encodes the regulatory component of mtOXPHOS Complex I and is essential for the assembly and enzymatic activity of Complex I. In contrast, NDUFB8 encodes a non- regulatory accessory subunit that is not involved in the catalysis of Complex I. The proposed studies should provide insight into the mechanism(s) involved in arsenic induced breast cancer and in the future may help prevent or treat breast cancers in female veterans.

描述（由申请人提供）： 由于大量妇女在军队中服役，因此越来越多的女性退伍军人受到乳腺癌的影响。这项研究的长期目标是开发针对乳腺癌的化学预防和治疗剂，以减轻女性军事人员的健康负担。这项研究的目前目标是确定参与砷引起的乳腺癌发展的机制。为了复制正常的野外暴露条件，我们将乳房上皮细胞暴露于低剂量的砷中几个月。我们发现，乳房上皮细胞连续暴露于砷中，导致细胞增殖增加，伤口愈合增加，锚固独立的生长增加以及增加的Matrigel侵袭。这些研究表明，砷会诱导乳腺上皮细胞的肿瘤性转化。我们的初步研究表明，线粒体是砷诱导转化的重要靶标。线粒体控制细胞生长和细胞死亡。线粒体执行其他细胞功能，包括通过线粒体氧化磷酸化（MTOXPHOS）产生ATP。我们发现，暴露于砷诱导5P染色体的选择性亚基因组扩增，其中包含许多参与线粒体功能的基因。与这一发现一致的砷转化细胞显示出1）复杂I和IV活性的增加； 2）复杂I调节亚基NDUFA13或GRIM19（与类维生素性干扰素诱导的死亡率相关的基因）和非调节性NDUFB8的表达增加； 3）增加包含复合物IV的Coxii亚基的表达增加。此外，我们的研究表明，砷处理不会1）诱导复杂II和III活性的变化，以及2）改变砷转运蛋白的表达。然而，砷转化的细胞产生的活性氧水平增加。我们假设砷会破坏乳腺上皮细胞的肿瘤性转化的mtoxphos功能。为了解决所提出的假设，我们计划：目标1：确定在进展过程中砷诱导的mtoxphos功能障碍（1、2、3、4个月），以对乳腺上皮细胞的肿瘤性转化（5个月）。 AIM 2：确定砷诱导的变化，影响乳腺上皮细胞的进展和肿瘤转化期间MTOXPHOS超复合物的亚基基因表达和组织。 AIM 3：确定mtoxphos复合物I在抗砷诱导的细胞死亡和肿瘤发育中的调节和非调节亚基的作用。 NDUFA13/grim19编码MTOXPHOS复合物I的调节成分，对于复合物的组装和酶活性是至关重要的。女退伍军人。

项目成果

Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function.

• DOI: 10.1038/s41419-018-0765-9
• 发表时间: 2018-07-20
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Singh B;Schoeb TR;Bajpai P;Slominski A;Singh KK
• 通讯作者: Singh KK

Human REV3 DNA Polymerase Zeta Localizes to Mitochondria and Protects the Mitochondrial Genome.

• DOI: 10.1371/journal.pone.0140409
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Singh B;Li X;Owens KM;Vanniarajan A;Liang P;Singh KK
• 通讯作者: Singh KK

Mitochondrial determinants of cancer health disparities.

• DOI: 10.1016/j.semcancer.2017.05.001
• 发表时间: 2017-12
• 期刊: Seminars in cancer biology
• 影响因子: 14.5
• 作者: Choudhury AR;Singh KK
• 通讯作者: Singh KK

Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.

• DOI: 10.1371/journal.pone.0139846
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Singh B;Owens KM;Bajpai P;Desouki MM;Srinivasasainagendra V;Tiwari HK;Singh KK
• 通讯作者: Singh KK

Single molecule mtDNA fiber FISH for analyzing numtogenesis.

用于分析神经发生的单分子 mtDNA 纤维 FISH。

• DOI: 10.1016/j.ab.2017.03.015
• 发表时间: 2018
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: Koo,Dal-Hoe;Singh,Bhupendra;Jiang,Jiming;Friebe,Bernd;Gill,BikarmS;Chastain,PaulD;Manne,Upender;Tiwari,HemantK;Singh,KeshavK
• 通讯作者: Singh,KeshavK