Publication: Proteostasis Based Molecular Approaches Alters Proteasomal Functions Can Deplete Misfolded Proteins Aggregation And Regulate Improper Cellular Proliferation
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2024-12-30
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Indian Institute of Technology, Jodhpur
Abstract
The ubiquitin-proteasome system (UPS) in cells is an essential cellular mechanism involved in the degradation of intracellular misfolded aggregated proteins, constituting a significant proteolytic pathway. It is involved in several essential cellular activities such as regulation of gene expression, cell cycle, cellular stress response, as well as proliferation and growth. Accumulation of misfolded proteins compromises overall cellular health and fitness. The accumulation of various inclusions serves as a clinical feature for neurodegenerative diseases. We reported that the natural disaccharide Trehalose treatment elevates endogenous proteasome levels and enhances the activities of the proteasome. Trehalose-mediated proteasomal activation elevates the removal of both bona fide misfolded and various neurodegenerative disease-associated proteins. Trehalose may retain a proteasome activation potential, which seems helpful in the solubilization of different mutant misfolded proteins, improving cell viability. Our results reveal a possible molecular approach to reduce the overload of intracellular misfolded proteins, and such cytoprotective functions may play a critical role against protein conformational diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended to treat moderate-to-severe pain. Previous studies suggest that NSAIDs can suppress cellular proliferation and elevate apoptosis in different cancer cells. Ketorolac is an NSAID and can reduce the cancer cells' viability. Further, we have observed that NSAID Ketorolac treatment disturbs proteasome functions, which induces the aggregation of aberrant ubiquitinated proteins. Ketorolac exposure also induced the aggregation of expanded polyglutamine proteins, resulting in cellular proteostasis disturbance. We found that the treatment of Ketorolac aggravates the accumulation of various cell cycle and apoptosis-linked proteins, which results in pro-apoptotic induction in cells. Ketorolac-mediated proteasome disturbance leads to mitochondrial abnormalities. Finally, we have observed that Ketorolac treatment depolarized mitochondrial membrane potential, leading to release of cytochrome c in cytoplasm, and induced apoptosis in cells, which could be due to proteasome functional depletion. Deeper research is needed to understand details of NSAIDs-based anti-proliferative molecular mechanisms that can elevate apoptosis in cancer cells and generate anti-tumor potential with the combination of putative cancer drugs.
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Kumar, Prashant (2020).Proteostasis Based Molecular Approaches Alters Proteasomal Functions Can Deplete Misfolded Proteins Aggregation And Regulate Improper Cellular Proliferation (Doctor's thesis).Indian Institute of Technology, Jodhpur