Dr. Goswami's laboratory is pursuing basic science research in the field of free radical biology and chemistry 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 DNA synthesis, 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) expression and activity. MnSOD activity regulates a “ROS switch” facilitating superoxide-signaling that promotes proliferation and signaling by hydrogen peroxide that supports quiescence. Based on an inverse correlation between MnSOD activity and glucose consumption during the cell cycle, we proposed MnSOD as 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 shift their metabolism from glycolysis to mitochondrial respiration. A shift in mitochondrial dynamics more towards mitochondrial fusion was associated with a higher mitochondrial respiration rate during chronological aging; mitochondrial fusion proteins, MFN1 and OPA1 regulate this process. Normal human fibroblasts nearing the end of their chronological lifespan stimulates proliferation and confer therapy resistance of cancer cells. Efforts are ongoing to better understand the molecular mechanisms regulating stromal aging and cancer therapy response.
In collaboration with the Department of Chemistry, we are also investigating the efficacy of repurposing of FDA approved antimalarial drug, artemisinin for mitochondrial delivery (currently hold a US patent for this newly synthesized drug) to selectively enhance toxicity of cancer cells to standard of care therapy.
- Sarsour et al., 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 et al., Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth. Aging Cell 2008, 7:405-417. PMID: 18331617 PMCID: PMC2538945.
- Sarsour et al., 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
- Son et al., Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging. Aging Cell 2017; PMID: 28758339
- Sarsour et al., Arachidonate 12-Lipoxygenase and 12-Hydroxyeicosatetraenoic acid contribute to stromal aging-induced progression of pancreatic cancer. J Biol Chem. 2020 May 15;295(20):6946-6957. doi: 10.1074/jbc.RA120.012798. PMID: 32265301
- Kalen et al., Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells. Antioxidants (Basel), 2020 Jan 26;9(2):108. doi: 10.3390/antiox9020108. PMID: 31991904; PMCID: PMC7070254