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

摘要/摘要 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 这些癌症是长期暴露在已知的环境致癌物质香烟烟雾和石棉中。他们 很难治疗，因为它们通常含有3000多个突变，这些突变来自于 致癌物质。通过新的突变和旁路途径可以绕过针对一个突变的目标。为了这个 原因是，以线粒体通路为靶点是一种重要的新方法，因为它们 位于致癌驱动蛋白和通路突变的下游。 最近，我们发现癌前病变的Barrett‘s食道细胞慢性暴露于胆盐诱导 通过一种机制进行恶性转化，这种机制被称为‘少数MOMP(线粒体外膜 渗透性)‘。MOMP受B细胞淋巴瘤-2(Bcl2)家族蛋白的调节，这些蛋白分为 与BH3(BH3)结构域相互作用的促和抗凋亡蛋白。少数民族MOMP部分 将细胞凋亡机制的内在途径激活到不会导致细胞死亡的水平，而是相反 促进基因组不稳定性、细胞转化和肿瘤发生。“少数族裔MOMP”也能抵抗细胞凋亡 通过上调抗凋亡蛋白Mcl-1。当我们瞄准Mcl-1时，少数民族MOMP改变了 从亚致死的线粒体激活到坦率的凋亡，肿瘤细胞死亡。不知道的是 少数民族MOMP机制是否从不同环境广泛促进恶变 致癌物质(烟雾和石棉)。目前，胸癌治疗的主要障碍是 克服对治疗的抗拒。如果少数族裔MOMP是一种促进 癌变的同时又能抵抗细胞凋亡，然后破坏少数人 靶向Bcl-2蛋白的MOMP为克服治疗难治性提供了一种治疗策略 癌症。 我们的目标是确定‘少数族裔MOMP’是否是一种可推广的致癌机制 环境致癌物质。我们将确定这一机制是否与 临床靶向的bcl2蛋白。正常情况下，致癌线粒体能够使癌细胞存活；如果亚 致命性激活的凋亡机制不受抑制，肿瘤细胞将不再抵抗凋亡。这些 线粒体的改变应该会恢复对治疗难治的胸癌的治疗敏感性。我们的 假说认为长期接触环境致癌物既能诱发致癌，又能产生抗药性。 通过少数民族MOMP诱导细胞凋亡。如果少数民族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，然后通过阻断少数人的MOMP而使其发生凋亡 代偿性抗凋亡蛋白提供了一种新的临床可操作的治疗策略。

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.