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: 10543157
• 负责人: Robert Taylor Ripley
• 金额: $ 18.33万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543157
• 关键词: Address; Apoptosis; Apoptotic; Asbestos; BCL-2 Protein; BCL2 gene; Barrett Esophagus; Bile Acids; Bypass; Carcinogens; Caspase; Cell Death; Cell Membrane Permeability; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Data; 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; Newly Diagnosed; 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 treatment; therapeutic target; therapy resistant; treatment strategy; tumor; tumor growth; 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 肺癌和间皮瘤在2020年占新诊断的200，000多例。之间的共同联系 这些癌症是长期暴露于已知的环境致癌物香烟烟雾和石棉。他们 是难以治疗的，因为它们通常具有来自细菌的重复损伤的超过3000个突变。 致癌物质。通过新的突变和旁路途径来规避靶向一个突变。为此 因此，靶向线粒体途径代表了一种重要而新颖的方法，因为它们 是致癌驱动蛋白和途径突变的下游。 最近，我们已经表明，慢性暴露前肿瘤，巴雷特食管细胞的胆盐诱导 通过称为“少数MOMP（线粒体外膜）”的机制恶性转化 透化作用MOMP受B细胞淋巴瘤-2（Bcl-2）蛋白家族调节，该蛋白家族分为 在Bcl-2同源性-3（BH 3）结构域相互作用的促凋亡蛋白和抗凋亡蛋白。少数MOMP部分 激活细胞凋亡机制的内在途径至不导致细胞死亡而是 促进基因组不稳定性、细胞转化和肿瘤发生。“少数MOMP”也抵抗细胞凋亡 通过抗凋亡蛋白Mcl-1的上调。当我们针对Mcl-1时，少数MOMP发生了变化 从亚致死的线粒体活化到明显的凋亡，肿瘤细胞死亡。不为人知的是 少数MOMP机制是否广泛促进了不同环境的恶性转化 致癌物质（烟雾和石棉）。目前，治疗胸部癌症的主要障碍是 克服对治疗的抗拒如果少数MOMP是一种促进 致癌作用，同时使细胞凋亡的阻力，然后破坏少数 通过靶向Bcl-2蛋白的MOMP提供了一种治疗策略，以克服治疗难治性 癌的 目的是确定“少数MOMP”是否是一种可推广的致癌机制， 环境致癌物。我们将确定这一机制是否与上调 可临床靶向的Bcl-2蛋白。正常情况下，致癌线粒体使癌细胞存活;如果亚 如果凋亡机制的致死性激活未被抑制，则肿瘤细胞将不再抵抗凋亡。这些 线粒体改变应该恢复对治疗难治性胸癌的治疗敏感性。我们 一种假说认为，长期暴露于环境致癌物可诱导致癌作用和耐药性 通过Minority MOMP进行细胞凋亡。如果少数MOMP是一种需要上调的致癌机制， 抗凋亡蛋白对癌细胞存活的影响，然后通过阻断 补偿性抗凋亡蛋白提供了一种新的临床可行的治疗策略。