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Ibuprofen Induces Mitochondrial-Mediated Apoptosis Through Proteasomal Dysfunction

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Abstract

In routine course of life, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed antipyretic, analgesic, and anti-inflammatory drugs. It is a well-proposed notion that treatment of NSAIDs may induce anti-proliferative effects in numerous cancer cells. Ibuprofen from isobutylphenylpropanoic acid is NSAID and used to relieve fever, pain, and inflammation. It is also used for juvenile idiopathic arthritis, rheumatoid arthritis, patent ductus arteriosus, and for pericarditis. Despite few emerging studies have expanded the fundamental concept that the treatment of NSAIDs influences apoptosis in cancer cells, however the NSAID-mediated precise mechanisms that determine apoptosis induction without producing adverse consequences in variety of cancer cells are largely unknown. In our present study, we have observed that ibuprofen reduces proteasome activity, enhances the aggregation of ubiquitylated abnormal proteins, and also elevates the accumulation of crucial proteasome substrates. Ibuprofen treatment causes mitochondrial abnormalities and releases cytochrome c into cytosol. Perhaps, the more detailed study is needed in the future to elucidate the molecular mechanisms of NSAIDs that can induce apoptosis without adverse effects and produce effective anti-tumor effects and consequently help in neurodegeneration and ageing.

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Acknowledgments

This work was supported by the Department of Biotechnology, Government of India. AM was supported by Ramalinganswami Fellowship (BT/RLF/Reentry/11/2010) and Innovative Young Biotechnologist Award (IYBA) scheme (BT/06/IYBA/2012) from the Department of Biotechnology, Government of India. AU and VJ were supported by research fellowship from University Grants Commission, Council of Scientific and Industrial Research, Government of India. The authors would like to thank Mr. Bharat Pareek for his technical assistance and entire lab management during the manuscript preparation. We would also thank all for gifted plasmids: Dr. Nihar Ranjan Jana (National Brain Research Centre, Manesar, Gurgaon, India) for pd1EGFP plasmid, Dr. I. M. Verma (Salk Institute for Biological Studies, La Jolla, CA, USA) for pCMX-IκBα plasmid, Dr. Aleem Siddiqui (UC San Diego, Gilman Dr. La Jolla, CA) for p3x-κB-Luc plasmid, Dr. Lois Greene (Laboratory of Cell Biology, NHLBI, NIH, Bethesda, MD) for the pEGFP hsp70 construct, Dr. Ted Dawson (Johns Hopkins University Institute for Cell Engineering, North Broadway St. Baltimore, MD, USA) for pRK5-HA-Ubiquitin-WT plasmid, Dr. Csaba Soti (Department of Medical Chemistry, Semmelweis University, Budapest, Hungary) for GFP-wtCAT plasmid, Dr. Ron R. Kopito (Stanford University Biology Department Lorry Lokey Bldg Campus Drive Stanford CA) for pEGFP-C1 CFTRΔF508 plasmid, Dr. Nico Dantuma (Karolinska Institutet, Department of Cell and Molecular Biology, Stockholm, Sweden) for the GFP-Ubiquitin plasmid, and Dr. A Tunnacliffe (Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK) for EGFP-HDQ23 and EGFP-HDQ74 constructs.

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  1. Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India, 342011

    Arun Upadhyay, Ayeman Amanullah, Deepak Chhangani, Vibhuti Joshi, Ribhav Mishra & Amit Mishra

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  1. Arun Upadhyay
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Upadhyay, A., Amanullah, A., Chhangani, D. et al. Ibuprofen Induces Mitochondrial-Mediated Apoptosis Through Proteasomal Dysfunction. Mol Neurobiol 53, 6968–6981 (2016). https://doi.org/10.1007/s12035-015-9603-6

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