Dr. St. Clair’s
research focuses on investigating the fundamental mechanisms by which reactive
oxygen species (ROS) and reactive nitrogen species (RNS) contribute to normal
tissue injury and cancer formation. Her laboratory is the first to clone the
human gene for the primary superoxide removal enzyme in the mitochondria,
manganese superoxide dismutase (MnSOD), and this 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. She has made the seminal observation that
expression of MnSOD suppresses neoplastic transformation and promotes
differentiation of cancer cells, leading to a reduction in the tumorigenicity
and metastatic capability of cancer cells. Her work has led to a paradigm shift
in the thinking about the role of antioxidants in cancer therapy.
Chemotherapy-induced side effects to normal
tissues are a major problem limiting the success of cancer therapy. The ability
of normal tissues to tolerate these side effects frequently imposes a limit on
the dose of the anticancer agent that can be given safely to the patient, which
in turn limits the probability of a cure. Dr. St. Clair has recently expanded
her research in the area of antioxidant defense into a program project on the
role of oxidative stress in drug-induced normal tissue injury including
chemotherapy-induced cognitive impairment.
Therapy-induced acute myeloid leukemia
(t-AML), therapy-induced myelodysplastic syndrome (t-MDS), and therapy-induced
myeloproliferative neoplasm (t-PMN), are increasingly common in patients receiving
radiation or chemotherapy, due, in part, to increasingly aggressive cancer
treatments. It has been shown that radiation and nearly fifty percent of the
current FDA-approved chemotherapeutic drugs exert a tumor killing effect, in
part, by generation of ROS. Depending on the levels of ROS and the local
cellular environment, ROS can exhibit cytotoxic or cytoprotective effects by
regulating cellular signaling pathways. An important mediator of ROS-mediated
action is the proinflammatory cytokine tumor necrosis factor (TNFa), which has been
shown to play an important role in the development of t-MDS. Dr. St. Clair is
investigating how hematopoietic stem cells (HSC) and hematopoietic precursor
cells (HPC) differentially utilize the ROS-mediated signals to trigger
development of t-MDS and subsequent progression to leukemia.
1095 VA Drive
University of Kentucky
Lexington, Kentucky 40536
- Yen HC, Oberley TD, Vichitbanda S, Ho YS, St. Clair DK. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest 98:1253-1260, 1996.
- Majima HJ, Oberley TD, Furakawa K, Mattson MP, Yen HC, Szweda LI, St. Clair DK. Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death. J Biol Chem 273:8217-8224, 1998.
- Zhao Y, Chaiswing L, Oberley TD, Batinic-Haberle I, St. Clair WH, Epstein CJ, St. Clair DK. A mechanism-based antioxidant approach for the reduction of skin carcinogenesis. Cancer Res 65:1401-1405, 2005.
- Lien YC, Noel T, Liu H, Stromberg AJ, Chen KC, St. Clair DK. Phospholipase C-delta1 is a critical target for TNF receptor-mediated protection against adriamycin-induced cardiac injury. Cancer Res 66:4329-4338, 2006.
- Dhar SK, Tangpong J, Chaiswing L, Oberley TD, St. Clair DK. Manganese superoxide dismutase is a p53-regulated gene that switches cancers between early and advanced stages. Cancer Res. 71:6684-6695, 2011.
Five Most Recent Publications (an automated list via PubMed, based on researcher's ID and University of Kentucky)
|1. ||Kinugasa H, Whelan KA, Tanaka K, Natsuizaka M, Long A, Guo A, Chang S, Kagawa S, Srinivasan S, Guha M, Yamamoto K, St Clair DK, Avadhani NG, Diehl JA, Nakagawa H.|
Mitochondrial SOD2 regulates epithelial-mesenchymal transition and cell populations defined by differential CD44 expression.
Oncogene. 2015 Feb.
|2. ||Xu Y, Miriyala S, Fang F, Bakthavatchalu V, Noel T, Schell DM, Wang C, St Clair WH, St Clair DK.|
Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect.
Oncogene. 2014 Nov.
|3. ||Zhao Y, Miriyala S, Miao L, Mitov M, Schnell D, Dhar SK, Cai J, Klein JB, Sultana R, Butterfield DA, Vore M, Batinic-Haberle I, Bondada S, St Clair DK.|
Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment.
Free Radic Biol Med. 2014 Jul;72:55-65.
|4. ||Holley AK, Xu Y, Noel T, Bakthavatchalu V, Batinic-Haberle I, St Clair DK.|
Manganese superoxide dismutase-mediated inside-out signaling in HaCaT human keratinocytes and SKH-1 mouse skin.
Antioxid Redox Signal. 2014 May;20(15):2347-60.
|5. ||Breckwoldt MO, Pfister FM, Bradley PM, Marinković P, Williams PR, Brill MS, Plomer B, Schmalz A, St Clair DK, Naumann R, Griesbeck O, Schwarzländer M, Godinho L, Bareyre FM, Dick TP, Kerschensteiner M, Misgeld T.|
Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo.
Nat Med. 2014 May;20(5):555-60.