Dr. Goswami's laboratory is pursuing basic science research in the field of free radical biology of the mammalian cell cycle, aging and cancer. His laboratory first reported the presence of a “redox cycle” within the mammalian cell cycle that integrates cellular metabolism to cell cycle progression. Mitotic cells are at 3-4 fold higher oxidation state compared to G1-cells. Consistent with the concept of a redox cycle within the cell cycle, a prooxidant event was found to be necessary for the initiation of S-phase.
The redox cycle within the cell cycle is regulated by post-transcriptional (transcript selection) and post-translational (methylation/demethylation) modifications of manganese superoxide dismutase (MnSOD), an antioxidant enzyme that is localized in the mitochondria matrix. Changes in MnSOD activity during transition from quiescence to the proliferative cycle, and subsequently during progression through the cell cycle correlates with changes in the cell cycle regulatory proteins, cyclins and cyclin dependent kinase inhibitors, supporting the hypothesis that MnSOD activity regulates a “ROS switch” facilitating superoxide-signaling that promotes proliferation and signaling by hydrogen peroxide that supports quiescence. The periodic fluctuation of MnSOD activity during the cell cycle inversely correlates with cellular reactive oxygen species (ROS: superoxide and hydrogen peroxide) levels as well as glucose and oxygen consumption. Based on an inverse correlation between MnSOD activity and glucose consumption during the cell cycle, we proposed that MnSOD is a central molecular player for the “Warburg effect.”
Dr. Goswami’s laboratory first reported the discovery of a new mode of cellular aging (“chronological lifespan”) that is independent of mitotic division and telomerase activity. Chronological lifespan is defined as the duration of quiescence (G0-phase) during which normal human cells retain their capacity to re-enter the proliferative cycle and then exit back to quiescence. Normal cells nearing the end of their chronological lifespan exhibit a significant change in metabolism from glycolysis to mitochondrial respiration that were associated with increases in ATP and ROS levels. Older cells exhibit a lower bioenergetic health index (BHI) and they are more prone to oxidative injury. A shift in mitochondrial dynamics more towards mitochondrial fusion during aging is associated with increases in mitochondrial respiration; mitochondrial fusion proteins, MFN1 and OPA1 regulate this process.
The redox control of the cell cycle has a significant regulatory role in cancer cell response to therapy. Our results show cellular antioxidant status significantly contributes to therapy response of human breast, head-neck, and pancreatic cancer cells in vitro. Additional research efforts are ongoing to better understand the cellular and molecular mechanisms regulating cancer cell cycle phase-specific response to therapy. These efforts are based on a clinical study where the clinicians observed that the survival of head and neck cancer patients is significantly worse in patients with lower pre-therapy tumor F-18 Fluorothymidine (FLT) uptake (presumably due to a lower proliferative index) compared to patients with a higher FLT uptake (higher proliferative index). Research efforts are focused on investigating whether cell cycle phase specific changes in cellular metabolism and oxidation state regulate therapy response of cancer cells.
Research efforts related to aging and cancer are based on our recent observations of normal cells early in their chronological lifespan inhibiting proliferation of epithelial cancer cells and sensitize cancer cells to therapy, while normal cells nearing the end of their chronological lifespan enhance proliferation of epithelial cancer cells and confer resistance to therapy. Understanding the cellular and molecular mechanisms regulating this phenomenon is the primary focus of our current research.
The concept of a redox cycle integrating cellular metabolism to the cell cycle regulatory machinery is gaining acceptance from the scientific community. Because increasing evidence suggests that ROS have both beneficiary (normal physiological processes, e.g. cell cycle progression) and deleterious (cell death, pathological conditions, etc.) effects, we propose that “eustress” be used when discussing ROS processes that regulate normal physiological functions, while “oxidative stress” be used to discuss the deleterious effects of ROS.
- Menon SG, Sarsour EH, Spitz DR, Higashikubo R, Sturm M, Zhang H and Goswami PC. Redox regulation of the G1 to S transition in the mouse embryo fibroblast cell cycle. Cancer Research 2003, 63:2109-2117. PMID: 12727827.
- Sarsour EH, Agarwal M, Pandita TK, Oberley LW, and Goswami PC. Manganese superoxide dismutase protects the proliferative capacity of confluent normal human fibroblasts. J. Biol. Chem. 280:18033-18041, 2005. PMID: 15743756
- Menon SG, and Goswami PC. A redox cycle within the cell cycle: Ring in the old with the new. Oncogene 2007, 26:1101-1109. PMID: 16924237.
- Sarsour EH, Kalen AL, Venkataraman S, Oberley LW, and Goswami PC. Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth. Aging Cell 2008, 7:405-417. PMID: 18331617 PMCID: PMC2538945.
- Chaudhuri L, Nicholson AM, Kale AL, and Goswami PC. Preferential selection of MnSOD transcripts in proliferating normal and cancer cells. Oncogene 2012, 31(10):1207-1216. PMID: 21804600 PMCID: PMC3208126.
- Sarsour EH, Kalen AL, Xiao Z, Veenstra TD, Chaudhuri L, Venkataraman S, Reigan P, Buettner GR, and Goswami PC. Manganese superoxide dismutase activity regulates a metabolic switch during the mammalian cell cycle. Cancer Research 2012, 72:3807-3816. PMID: 22710435 PMCID: PMC3429130.
- Sarsour EH, Kalen AL, and Goswami PC. Manganese superoxide dismutase regulates a redox cycle within the cell cycle. Antioxidants & Redox Signaling 2014; 20(10):1618-1627. PMID: 23590434; PMC3942678
- Sarsour EH, Goswami M, Kalen AL, Lafin JT, and Goswami PC. Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast induced stimulation of breast cancer cell proliferation. AGE, 2014, 36:1213-1224. PMID 24691968; PMCID: PMC4082566
- Eckers JC, Kalen AL, Sarsour EH, Tompkins VS, Janz S, Son JM, Doskey CM, Buettner GR, and Goswami PC. Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells. Radiation Research, 2014, 182:420-429. PMID: 25229973; PMC4221113
- Son JM, Sarsour EH, Balaraju AK, Fussell J, Kalen AL, Wagner BA, Buettner GR, and Goswami PC. Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging. Aging Cell 2017; PMID: 28758339