INDIVIDUAL RESEARCHERJ. Andres Melendez , Ph.D.
Education1992 - Ph.D. from SUNY at Albany
1988 - Virginia Tech
|HT-1080 fibrosarcoma cells engineered to express a cytosolic form of the hydrogen peroxide detoxifying enzyme catalase and other redox-engineered cell lines have been used to demonstrate that SOD2 is a major source of the potent intracellular signaling molecule, hydrogen peroxide. The MMPs may represent just one family of genes whose expression is tightly regulated by Sod2-derived hydrogen peroxide.|
Reactive oxygen species (ROS) are major contributors to numerous disease conditions including arthritis, atheresclerosis, cancer, ischemia-reperfusion injury, nervous system disorders and the process of aging. ROS are comprised of a number of reduction products of oxygen and include superoxide, hydrogen peroxide and the hydroxyl radical. In the past decade it has emerged that these ROS are important in cellular signaling and metabolism. Thus, ROS contribute to disease but are also essential for intracellular signaling and metabolic processes. A variety of antioxidant enzymes have evolved to protect the cell from ROS-mediated damage and it is believed that the inability to combat oxidative stress is the determining factor between normal and diseased states. Studies in this laboratory focus on how mitochondrial-derived ROS and antioxidant enzymes regulate signaling transduction cascades, gene expression, cell growth, proliferation and ultimately tumor growth and metastases. Others and we have established that alterations in the mitochondrial production of reactive oxygen can have profound effects on tumor cell growth both in vivo and in vitro. Overexpression of the enzyme responsible for mitochondrial ROS detoxification, manganese superoxide dismutase (Sod2), inhibits tumor growth in some cases and enhances metastatic invasion in others. As a result of the enzymatic removal of superoxide by Sod2 hydrogen peroxide is generated and is responsible for both inhibiting cell growth and promoting metastasis. At present the laboratory is defining the ROS-dependent signaling pathways that distinguish between inhibition of tumor growth and enhanced stromal invasion or metastasis. We utilize state of the art cell, biochemical, microscopy and molecular methodologies to perform these studies. Our ultimate goal is to develop antioxidant-based gene therapies for the prevention and treatment of cancer. A Cadre of post-doctoral, graduate and undergraduate students and numerous outside collaborations are the foundation for these studies.
- Melillo AA, Bakshi CS, Melendez JA. Francisella tularensis antioxidants harness reactive oxygen species to restrict macrophage signaling and cytokine production. J Biol Chem. 2010 Sep 3;285(36):27553-60.
- Dasgupta J, Kar S, Liu R, Joseph J, Kalyanaraman B, Remington SJ, Chen C, Melendez JA. Reactive oxygen species control senescence-associated matrix metalloproteinase-1 through c-Jun-N-terminal kinase. J Cell Physiol. 2010 Oct;225(1):52-62.
- Kar S, Subbaram S, Carrico PM, Melendez JA. Redox-control of matrix metalloproteinase-1: a critical link between free radicals, matrix remodeling and degenerative disease. Respir Physiol Neurobiol. 2010 Dec 31;174(3):299-306.
- Melillo AA, Mahawar M, Sellati TJ, Malik M, Metzger DW, Melendez JA, Bakshi CS. Identification of Francisella tularensis Live Vaccine Strain CuZn Superoxide Dismutase as Critical for Resistance to Extracellular Generated Reactive OxygenSpecies. J Bacteriol. 2009 Aug 14. [Epub ahead of print] PubMed PMID: 19684141.
- Epperly MW, Melendez JA, Zhang X, Nie S, Pearce L, Peterson J, Franicola D, Dixon T, Greenberger BA, Komanduri P, Wang H, Greenberger JS. Mitochondrial targeting of a catalase transgene product by plasmid liposomes increases radioresistance in vitro and in vivo. Radiat Res. 2009 May;171(5):588-95. PubMed PMID: 19580494.
- Dasgupta J, Kar S, Van Remmen H, Melendez JA. Age-dependent increases in interstitial collagenase and MAP Kinase levels are exacerbated by superoxide dismutase deficiencies. Exp Gerontol. 2009 Aug;44(8):503-10. Epub 2009 May 3.PubMed PMID: 19409972.
- Hempel N, Ye H, Abessi B, Mian B, Melendez JA. Altered redox status accompanies progression to metastatic human bladder cancer. Free Radic Biol Med. 2009 Jan 1;46(1):42-50. Epub 2008 Oct 1. PubMed PMID: 18930813; PubMed Central PMCID: PMC2630461.
- 7: Connor KM, Hempel N, Nelson KK, Dabiri G, Gamarra A, Belarmino J, Van De Water L, Mian BM, Melendez JA. Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells. Cancer Res. 2007 Nov 1;67(21):10260-7. PubMed PMID: 17974967.