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.

Public Health Relevance

Overall mortality from cancer remains the second leading cause of death in the United States, and as such, new treatments and therapeutic targets are highly desired. Cancer cells develop a number of ways to escape cell death, including resistance to reactive oxygen species, which complicates treatment and ultimately, leads to chemo- and radio-resistance. This project aims to address a novel molecular mechanism at work within mitochondria that cancer cells may take advantage of to evade death in the face of such oxidative stress, which may provide insight into a new strategy for improving cancer cell killing.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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Virginia Commonwealth University
Schools of Medicine
United States
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