The primary research focus of this laboratory is in the area of the mitochondrial antioxidant defense system. We cloned the human gene for the primary superoxide removal enzyme in mitochondria, manganese superoxide dismutase (MnSOD), and the initial study has been expanded into several separate but related projects. These projects involve evaluating genetic abnormalities of antioxidant enzymes, the mechanisms regulating gene expression, and the impact these alterations have on the ability of humans to cope with oxidative stress. We made the seminal observation that expression of MnSOD in mitochondria suppresses neoplastic transformation and promotes differentiation of cancer cells, leading to a reduction in their tumorigenicity and metastatic capability. However, contradictory information in the literature based on random detection of MnSOD in cancer cells and human tissues resulted in confusion as to whether and when MnSOD expression is altered in cancer. To directly address this important question, we generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter/enhancer elements to investigate the changes of MnSOD transcription throughout the development of cancer. The results demonstrate that MnSOD expression was suppressed at a very early stage, but subsequently increased at late stages of skin carcinogenesis. Importantly, the decline in MnSOD expression occurred prior to the development of benign tumors and was concurrent with an increase in glucose utilization. The decline in MnSOD expression in the early stage of cancer was caused by a p53-mediated suppression of MnSOD transcription. However, as the tumor progresses and p53 activity is lost, MnSOD levels rise again, creating conditions in which cancer cells can survive under oxidative stress. The results identify MnSOD as a p53-regulated gene whose expression switches between early and advanced stages of cancer. We further demonstrated that MnSOD serves as a mitochondrial fidelity protein that protects the mitochondrial genome against oxidative stress-induced inactivation. Based on these critical findings, we are testing the hypothesis that defective MnSOD activity signals an adaptive response, leading to activation of a metabolic switch that initiates the Warburg effect, which is an important metabolic change that confers many growth and survival advantages to cancer cells, including a decrease of reactive oxygen species (ROS), a byproduct of mitochondrial energy metabolism.
In another research project, our work has led to a paradigm shift in the thinking about the role of antioxidants in cancer therapy. Using MnSOD transgenic and knockout mice, we have demonstrated the important roles of MnSOD in the regulation of cell proliferation and cell death, which, in turn, modulate subsequent tumor formation. The most important outcome from these results is the knowledge that MnSOD inhibits both apoptosis and proliferation induced by ROS-generating carcinogens when given prior to exposure to carcinogens; when MnSOD mimetic is applied after the peak of apoptosis and before the peak of proliferation, the MnSOD mimetic can inhibit ROS-induced proliferation without suppressing ROS-induced apoptosis. The window between apoptosis and proliferation provides an opportunity to utilize an antioxidant intervention that selectively suppresses cell proliferation without interfering with apoptosis. These findings, coupled to our original finding that excessive ROS play an important role in mediating normal tissue injury caused by established chemotherapeutics, reveal a novel strategy that could be exploited for either developing antioxidant-based cancer prevention or sensitizing cancer cells to radiation- or chemo-based therapies.
Generation of ROS is a major mechanism responsible for the therapeutic effect of ionizing radiation and nearly 50% of chemotherapeutic drugs. Currently, these therapeutic strategies are being used to kill cancer cells without the benefit of a rational design that exploits the intrinsic differences in the cellular redox status of normal cells and cancer cells. Cancer cells are usually under higher oxidative stress than normal cells and it is known that an additional increase in prooxidant level can trigger cell death. Thus, therapeutic approaches that use redox active antioxidants that push tumor cells into oxidative stress overload but stimulate adaptive responses in normal cells can be developed to selectively enhance the efficient killing of cancer cells by radiation/chemotherapy. We are developing a novel dual-purpose drug approach that would not only improve the efficacy of cancer therapy but could also improve quality of life for cancer survivors by protecting normal tissue from ROS-generating therapeutics.
Over the past several years, we have assembled a team of investigators in a series of studies that move between bench and bedside, leading to a novel model of ROS-induced cognitive and cardiac dysfunction. Our model proposes that, in addition to the direct ROS-mediated mitochondrial injury in cardiac tissue, there is an indirect mechanism for drug-induced injury common to both cardiac and CNS tissues that results from a cytokine-mediated chain of events triggered by Drug-induced oxidative modification of proteins. This team project is based on our initial studies, which demonstrated that oxidative damage precedes nitrative damage in cardiac tissue treated with ROS generating chemotherapeutic drug including Doxorubicin, Dox and that animals deficient in both TNF receptors I and II suffer cardiac injury when exposed to Dox. Using mitochondria arrays and redox proteomics, we identified 4-hydroxynonenal (HNE)-bound mitochondrial proteins, which reveals a systemic effect on energy metabolism after Dox treatment. This team project is designed to identify practice- changing therapy through an integrated program of carefully coordinated mechanistic, intervention, and translational studies with the potential to limit currently devastating tissue toxicities that compromise critical physiological functions. Such advances may significantly improve the lives of cancer survivors.
Serious long-term therapy-induced impairment among cancer survivors is a currently understudied facet of cancer treatment, but one that is emerging as a critical need given clincial successes with certain cancers and treatment modalities. Our current research direction, based on in-depth understandings from this decades-long focus, into antioxidant defense mechanisms that have intriguing potential to address the challenge of serious post-survival impairment. Our overarching goal is to develop a novel dual-purpose drug approach to be used as a component of combination therapy to 1) improve the efficacy of existing cancer therapeutic protocols and 2) reduce the toxic side effects to normal tissues caused by existing therapeutic strategies. This dual-purpose approach to therapeutics is expected not only to enhance treatment efficacy and thereby increase patient survival but also simultaneously to improve quality of life among cancer survivors.
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