Environmental Carcinogens Induce Minority MOMP to Initiate Carcinogenesis in Lung Cancer and Mesothelioma whileMaintaining Apoptotic Resistance via Mcl-1

环境致癌物诱导少数 MOMP 引发肺癌和间皮瘤的癌变，同时通过 Mcl-1 维持细胞凋亡抵抗

• 批准号: 10356565
• 负责人: Robert Taylor Ripley
• 金额: $ 22.44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356565
• 关键词: Address; Apoptosis; Apoptotic; Asbestos; BCL-2 Protein; BCL2 gene; Barrett Esophagus; Bile fluid; Bypass; Carcinogens; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Data; Diagnosis; Environmental Carcinogens; Environmental Exposure; Exposure to; Family; Genomic Instability; Goals; Human; Induction of Apoptosis; Link; Lung; MCL1 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thorax; Measurable; Membrane Potentials; Mesothelial Cell; Mesothelioma; Minority; Mission; Mitochondria; Mitochondrial Proteins; Modeling; Mutate; Mutation; Normal tissue morphology; Oncogenic; Organoids; Outer Mitochondrial Membrane; Pathway interactions; Patients; Pharmaceutical Preparations; Predisposition; Process; Protein Family; Proteins; Public Health; Refractory; Research; Resected; Resistance; Role; Second Primary Cancers; Smoke; Smoking; Specimen; Stimulus; Survival Rate; Techniques; Testing; Therapeutic; Time; United States National Institutes of Health; Up-Regulation; advanced disease; bile salts; cancer cell; carcinogenesis; carcinogenicity; cell injury; cigarette smoke; clinically actionable; cytochrome c; exposure to cigarette smoke; human tissue; inhibitor; innovation; metabolomics; metaplastic cell transformation; mitochondrial membrane; neoplastic; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; protein function; refractory cancer; small hairpin RNA; targeted agent; targeted treatment; therapeutic target; therapy resistant; treatment strategy; tumor; tumorigenesis

ABSTRACT / SUMMARY Lung cancer and mesothelioma accounted for over 200,000 new diagnoses in 2020. The common link between these cancers is chronic exposure to the known environmental carcinogens cigarette smoke and asbestos. They are difficult to treat because they typically harbor over 3000 mutations from the repeated insults from carcinogens. Targeting one mutation is circumvented through new mutations and bypass pathways. For this reason, targeting the mitochondrial pathways represents an important and novel approach because they are downstream of oncogenic driver proteins and pathway mutations. Recently, we have shown that chronic exposure of pre-neoplastic, Barrett’s esophageal cells to bile salt induced malignant transformation through a mechanism termed, ‘Minority MOMP (mitochondrial outer membrane permeabilization)’. MOMP is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins that are divided into pro- and anti-apoptotic proteins that interact at Bcl-2 homology-3 (BH3) domains. Minority MOMP partially activates the intrinsic pathway of the apoptotic machinery to levels that do not result in cell death but instead promote genomic instability, cellular transformation, and tumorigenesis. ‘Minority MOMP’ also resists apoptosis through the upregulation of the anti-apoptotic protein, Mcl-1. When we targeted Mcl-1, Minority MOMP shifted from the sub-lethal mitochondrial activation to frank apoptosis and the tumor cells died. What is not known is whether the Minority MOMP mechanism widely promotes malignant transformation from different environmental carcinogens (smoke and asbestos). Currently, the major obstacle in the treatment of thoracic cancers is overcoming resistance to therapy. If Minority MOMP is a common mechanism that promotes carcinogenesis while simultaneously enabling resistance to apoptosis, then disruption of Minority MOMP by targeting Bcl-2 proteins provides a therapeutic strategy to overcome treatment-refractory cancers. The goal is to determine whether ‘Minority MOMP’ is a generalizable, oncogenic mechanism associated with environmental carcinogens. We will determine whether this mechanism is associated with upregulation of clinically-targetable bcl-2 proteins. Normally, the oncogenic mitochondria enable cancer cell survival; if the sub- lethal activation of the apoptotic machinery is unchecked, the tumor cell will no longer resist apoptosis. These mitochondrial alterations should restore therapeutic susceptibility to treatment-refractory, thoracic cancers. Our hypothesis is that chronic exposure of environmental carcinogens induces both carcinogenesis and resistance to apoptosis through Minority MOMP. If Minority MOMP is an oncogenic mechanism that requires upregulation of anti-apoptotic proteins for cancer cell survival, then shifting Minority MOMP to apoptosis by blocking the compensatory anti-apoptotic proteins provides a novel and clinically-actionable treatment strategy.

摘要/总结 2020 年，肺癌和间皮瘤新诊断病例超过 20 万例。两者之间的共同联系 这些癌症是由于长期接触已知的环境致癌物香烟烟雾和石棉而引起的。 很难治疗，因为它们通常含有 3000 多种突变，这些突变是由反复的侮辱造成的 为此，可以通过新的突变和旁路途径来规避针对一种突变的情况。 因此，针对线粒体途径代表了一种重要而新颖的方法，因为它们 是致癌驱动蛋白和突变途径的下游。 最近，我们发现，肿瘤前巴雷特食管细胞长期暴露于胆盐会诱导 通过称为“少数 MOMP（线粒体外膜）”的机制进行恶性转化 MOMP 受 B 细胞淋巴瘤-2 (Bcl-2) 蛋白家族的调节，该蛋白家族分为以下几类： 在 Bcl-2 同源性 3 (BH3) 结构域部分相互作用的促凋亡蛋白和抗凋亡蛋白。 激活细胞凋亡机制的内在途径，使其达到不会导致细胞死亡而是导致细胞死亡的水平 促进基因组不稳定、细胞转化和肿瘤发生，“少数 MOMP”也能抵抗细胞凋亡。 通过上调抗凋亡蛋白 Mcl-1，当我们靶向 Mcl-1 时，少数 MOMP 发生变化。 从亚致死线粒体激活到直接凋亡和肿瘤细胞死亡，目前尚不清楚。 少数MOMP机制是否广泛促进不同环境的恶性转化 目前，治疗胸部癌症的主要障碍是致癌物（烟雾和石棉）。 如果少数 MOMP 是促进治疗的常见机制。 致癌作用，同时能够抵抗细胞凋亡，然后破坏少数民族 MOMP 通过靶向 Bcl-2 蛋白提供了一种克服治疗难治性的治疗策略 癌症。 目标是确定“少数 MOMP”是否是一种与以下疾病相关的普遍致癌机制： 我们将确定这种机制是否与环境致癌物质的上调有关。 临床上可靶向的 bcl-2 蛋白通常可以使癌细胞存活； 如果细胞凋亡机制的致命激活不受控制，肿瘤细胞将不再抵抗细胞凋亡。 线粒体的改变应该可以恢复对难治性胸部癌症的治疗敏感性。 假设长期接触环境致癌物会诱发致癌和耐药 如果少数 MOMP 是一种需要上调的致癌机制。 抗凋亡蛋白促进癌细胞存活，然后通过阻断少数 MOMP 将其转变为细胞凋亡 补偿性抗凋亡蛋白提供了一种新颖且临床可行的治疗策略。