STAT3 Interacts with Cyclophilin D in Cancer Cells to Regulate the MPTP

描述（由申请人提供）：尽管癌症检测和治疗取得了重大进展，但对新的治疗靶点的需求仍然一如既往地突出。治疗的进步取决于对癌症中细胞生长增强、复制不朽和避免细胞死亡背后的复杂机制的更彻底的理解。根据这种想法，人们对更好地理解活性氧（ROS）在驱动肿瘤发生中的作用以及癌细胞如何能够在这种氧化环境中不仅持续存在而且茁壮成长越来越感兴趣。这种氧化应激主要是线粒体在能量产生中的正常功能的副产品。有趣的是，线粒体还充当细胞的氧化应激传感器，因此，ROS升高导致线粒体通透性过渡孔（MPTP）的激活和打开。MPTP横跨线粒体内外膜，连接线粒体基质和细胞质，其持续开放通常会导致线粒体肿胀、功能障碍，并最终通过线粒体外膜破裂导致细胞死亡。然而，尽管在癌细胞中观察到氧化还原状态的改变，但MPTP似乎更耐激活和打开。对癌症中MPTP不敏感背后的生化机制的研究可能会进一步深入了解癌细胞如何逃避细胞死亡，并可能为药物开发提供新的治疗靶点。最近有证据表明，在多种人类癌症中被组成性激活的蛋白质——转录信号换能器和激活因子3 （STAT3）存在于线粒体中，在那里它具有不同于其核功能的新作用。我们的初步数据已经确定，应激后线粒体STAT3与MPTP的关键调节剂和激活剂亲环蛋白D （CypD）相互作用，并且这种关联在癌细胞中更强、更持久。此外，我们还观察到，在癌细胞与化疗药物一起培养后，STAT3的线粒体池及其与CypD的结合选择性增加，这些化疗药物已知会诱导ROS作为其凋亡程序的一部分。因此，我们怀疑线粒体STAT3及其与CypD的相互作用可能对氧化应激诱导的癌细胞死亡具有保护作用。因此，拟议研究的目的是确定：1)氧化应激下STAT3与CypD的结合是如何介导的，这种相互作用是否导致MPTP开放减少，2)阻断这种相互作用是否会导致氧化肿瘤环境中癌细胞存活降低，以及随后的治疗是否会增加ROS损伤。这些问题的答案将提供对线粒体STAT3驱动癌细胞存活的新机制的深入了解，这种机制可以用于治疗目的。

DESCRIPTION (provided by applicant): Despite major advances in cancer detection and treatment, the need for novel therapeutic targets remains as prominent as ever. The advancement of treatment depends upon a more thorough understanding of the complex mechanisms at work behind the enhanced cell growth, replicative immortality, and avoidance of cell death seen in cancer. In line with this thinking, there is increasing interest in better understanding the role that reactive oxygen species (ROS) play in driving tumorigenesis and how cancer cells are able to not only persist but also thrive in this oxidative environment. This oxidative stress is predominately the by-product of the normal function of the mitochondrion in energy production. What's interesting is that mitochondria also serve as the oxidative stress sensor of the cell, whereby elevated ROS leads to activation and opening of the mitochondrial permeability transition pore (MPTP). Sustained opening of the MPTP, which spans the inner and outer mitochondrial membranes to link the mitochondrial matrix with the cytosol, normally leads to mitochondrial swelling, dysfunction, and ultimately, cell death via outer mitochondrial membrane rupture. However, in spite of the altered redox state observed in cancer cells it would appear that the MPTP is more resistant to activation and opening. Investigation into the biochemical mechanisms behind this insensitivity of the MPTP in cancer may provide further insight into how cancer cells escape cell death and provide, potentially, a novel therapeutic target for drug development. There is recent evidence that signal transducer and activator of transcription 3 (STAT3), a protein that is constitutively activated in a wide variety of human cancers, is present in the mitochondria where it has a novel role distinct from its nuclear function. Our preliminary data has determined that following stress mitochondrial STAT3 interacts with Cyclophilin D (CypD), the key regulator and activator of the MPTP, and this association is stronger and more sustained in cancer cells. Furthermore, we have observed a selective increase in the mitochondrial pool of STAT3 and its binding to CypD following incubation of cancer cells in culture with chemotherapeutic agents known to induce ROS as part of their apoptotic program. As a result, we suspect that mitochondrial STAT3 and its interaction with CypD may be protective against oxidative stress induced cell death in cancer cells. As a result, the aims of the proposed studies are to determine: 1) how binding of STAT3 to CypD under oxidative stress is mediated and if this interaction leads to decreased MPTP opening, and 2) if blockade of this interaction leads to decreased cancer cell survival in the oxidative tumor environment and following treatments that also increase the ROS insult. The answers to these questions will provide insight into a novel mechanism through which mitochondrial STAT3 could be driving cancer cell survival that could be taken advantage of for the purposes of therapy.