Ketorolac disturbs proteasome functions and induces mitochondrial abnormality-associated apoptosis

Abstract

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. However, molecular mechanisms by which Ketorolac can induce apoptosis and be helpful as an anti-tumor agent against carcinogenesis are unclear. Here, we observed treatment with Ketorolac disturbs proteasome functions, which induces aggregation of aberrant ubiquitinated proteins. Ketorolac exposure also induced the aggregation of expanded polyglutamine proteins, results cellular proteostasis disturbance. We found that the treatment of Ketorolac aggravates the accumulation of various cell cycle-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, released cytochrome c into cytoplasm, and induced apoptosis in cells, which could be due to proteasome functional depletion. Perhaps more in-depth research is required to understand the details of NSAID-based anti-proliferative molecular mechanisms that can elevate apoptosis in cancer cells and generate anti-tumor potential with the combination of putative cancer drugs.