Indomethacin elicits proteasomal dysfunctions develops apoptosis through mitochondrial abnormalities

• Published in: Journal of cellular physiology Vol. 233; no. 2; pp. 1685 - 1699
• Main Authors: Amanullah, Ayeman, Mishra, Ribhav, Upadhyay, Arun, Reddy, Pothula P., Das, Ranabir, Mishra, Amit
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-02-2018
• Subjects: A549 Cells; Abnormalities; Accumulation; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Apoptosis - drug effects; Cancer; Carcinogenesis; Carcinogens; Cercopithecus aethiops; COS Cells; Cyclooxygenase-2; Development strategies; Dose-Response Relationship, Drug; Fever; Humans; Indomethacin; Indomethacin - chemistry; Indomethacin - pharmacology; Inflammation; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; mitochondrial abnormalities; Molecular Docking Simulation; Nonsteroidal anti-inflammatory drugs; nonsteroidal anti‐inflammatory drugs (NSAIDs); Pain; proteasome; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Proteasomes; Protein Aggregates; Protein Binding; Proteins; Proteolysis; Signal Transduction - drug effects; Structure-Activity Relationship; Substrates; Time Factors; Ubiquitin; Ubiquitination; proteasome; apoptosis; nonsteroidal anti-inflammatory drugs (NSAIDs); mitochondrial abnormalities; indomethacin
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26081

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are a class of drugs that are mainly used to treat pain, inflammation, and fever via cyclooxygenase‐2 (COX‐2) inhibition. There are abundant findings that uncover the hidden critical chemotherapeutics potential of NSAIDs in cancer treatment. However, still the precise mechanism by which NSAIDs could be used as an effective anti‐tumor agent in the prevention of carcinogenesis is not well understood. Here, we show that indomethacin, a well‐known NSAID, induces proteasomal dysfunction that results in accumulation of unwanted proteins, mitochondrial abnormalities, and successively stimulate apoptosis in cells. We observed the interaction of indomethacin with proteasome and noticed the massive accumulation of intracellular ubiquitin‐positive proteins, which might be due to the suppression of proteasome activities. Furthermore, we also found that exposure of indomethacin causes the accumulation of critical proteasomal substrates that consequently generate severe mitochondrial abnormalities and prompt up key apoptotic events in cells. Our results demonstrate how indomethacin affects normal proteasomal functions and induces mitochondrial apoptosis in cells. These findings also improve our current understanding of how NSAIDs can exhibit crucial anti‐proliferative effects in cells. In near future, our findings may suggest a new possible strategy for the development of specific proteasome inhibitors in conjunction with other chemo‐preventive anticancer agents.
Indomethacin induces apoptosis through the disturbance of proteasome functions.