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

描述（由申请人提供）：尽管在癌症检测和治疗方面取得了重大进展，但对新型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增强细胞生长、复制永生和避免癌症中细胞死亡背后复杂机制的更透彻理解。与这种想法相一致，人们越来越有兴趣更好地了解活性氧（ROS）在驱动肿瘤发生中所发挥的作用，以及癌细胞如何不仅能够在这种氧化环境中生存而且能够茁壮成长。这种氧化应激主要是能量产生中的线粒体正常功能的副产物。有趣的是，线粒体也作为细胞的氧化应激传感器，由此升高的ROS导致线粒体渗透性转换孔（MPTP）的激活和开放。MPTP的持续开放，其跨越线粒体内膜和外膜以将线粒体基质与细胞质连接，通常导致线粒体肿胀、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改变，但似乎MPTP对激活和开放更具抗性。对癌症中MPTP不敏感性背后的生化机制的研究可能会进一步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，信号转导子和转录激活子3（STAT 3），一种在多种人类癌症中组成性激活的蛋白质，存在于线粒体中，在线粒体中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的关键调节因子和激活因子亲环素D（CypD）相互作用，并且这种关联在癌细胞中更强，更持久。此外，我们已经观察到选择性增加的线粒体池的STAT3和它的结合CypD的培养物中的癌细胞与化疗剂孵育后，已知诱导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的相互作用可能对癌细胞中氧化应激诱导的细胞死亡具有保护作用。因此，所提出的研究的目的是确定：1）在氧化应激下如何介导STAT3与CypD的结合，以及这种相互作用是否导致MPTP开放减少，以及2）这种相互作用的阻断是否导致氧化肿瘤环境中癌细胞存活减少，以及在也增加ROS损伤的治疗之后。这些问题的答案将提供一种新的机制，通过这种机制，线粒体STAT3可以驱动癌细胞存活，从而可以利用这种机制进行治疗。

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.