SEMINAR: Tumor-specific Regulation of MnSOD: Towards targeted "oxidation therapy" in estrogen negative breast cancer
|Tumor-specific Regulation of MnSOD: Towards targeted "oxidation therapy" in estrogen negative breast cancer : School of Anatomy, Physiology & Human Biology Seminar Series
The Seminar: Compelling evidence suggests that cancer cells are generally under reactive oxygen species (ROS) stress. As mitochondria respiration is the main source of ROS generation in the cells, MnSOD is of prime importance in maintaining the tumor cellular ROS balance. It has recently been reported that generation of ROS is closely involved in PPAR ligand–induced apoptosis. However, the mechanism by which these ligands induce ROS generation remains unknown. We report the identification of human MnSOD as a PPAR target gene and that activation by PPAR agonists led to downregulation of MnSOD gene expression in vitro and in vivo xenograft model. Futhermore, histopathologic analysis of breast cancer biopsies obtained from patients treated with synthetic PPAR agonists also showed MnSOD repression. Repression of MnSOD expression was accompanied with increase in intracellular superoxide production in breast cancer cells. Suppression of MnSOD levels by small-interfering RNA or activation of PPAR in breast cancer cells increased oxidative stress and enhanced chemo-sensitivity to ROS-inducing drugs such as docetaxel and doxorubicin. Importantly, normal breast cells were completely refractory to these effects. Together, our data not only identifies MnSOD as a novel PPAR target but also provides a molecular mechanism for ROS-manipulation therapy through the intelligent use of PPAR ligands in combination with ROS-inducing drugs to preferentially kill cancer cells.
The Speaker: Dr. Alan Prem Kumar earned his Ph.D. from University of North Texas, USA. From his Ph.D. work, he discovered a novel regulatory protein, PyrR for the pyrimidine biosynthetic pathway in Pseudomonas. Because pyrimidine biosynthesis is an essential step in the progression of secondary Pseudomonas infections, PyrR presents an attractive anti-pseudomonal drug target. Dr. Kumar then pursued Postdoctoral training in Cancer Research at Sidney Kimmel Cancer Center, California, USA. He was awarded a Postdoctoral Fellowship for his work on the role of nuclear receptors in the transcriptional regulation of human myeloperoxidase, a leukocyte enzyme implicated as causative agent in atherosclerosis and Alzheimer’s disease. Dr. Kumar relocated back to Singapore to join the Faculty of Medicine, National University of Singapore as an independent Principal Investigator to continue on his expertise on nuclear receptor and cancer biology. His current research interest includes the role of nuclear receptors involved in the regulation of target genes and to elucidate mechanism and associated signal pathways. Another area of interest is to have a greater understanding of these nuclear receptors – aimed at developing newer selective PPAR gamma modulators, drugs with more potent activity and less toxicity. Towards this end, Dr Kumar identified a series of 21 structurally new PPAR gamma activators by computer-aided drug design using a combination of ligand-based and structure-based approaches. In collaboration with GenoMed, Inc, USA, he has recently identified a new tyrosine kinase involved in the progression of ovarian, breast, and prostate cancers. Inhibitors were developed against this kinase using computer-aided drug design. His goal is to use these drugs to demonstrate its effectiveness in a variety of cancer cell lines, mouse xenograft, with intent to clinical trials here in Singapore. Over the years, Dr. Kumar and his laboratory have forged relationships with scientists in cancer research and with cancer advocacy groups in Singapore.
Host: E/Prof Dharmarajan - PH) 6488 2981
Dr Alan Prem Kumar, Assistant Professor, Cancer Science Institute of Singapore; Dept of Pharmacology, National University of Singapore
Room 1.81, Anatomy, Physiology & Human Biology Building North, UWA
: 6488 3313
Wed, 30 May 2012 13:00
Wed, 30 May 2012 14:00
Debbie Hull <[email protected]>
Thu, 10 May 2012 11:46
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