Protein disulfide isomerase inhibits endoplasmic reticulum stress response and apoptosis via its oxidoreductase activity in colorectal cancer |
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| Institution: | 1. Department of Pharmaceutical and Administrative Sciences, College of Pharmacy, Western New England University, United States;2. Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Harvard Medical School, United States;1. University of Bonn, Institute of Pharmacy, Department of Clinical Pharmacy, An der Immenburg 4, 53121 Bonn, Germany;2. University of Cologne, Cologne Biocenter, Zülpicherstraße 47b, 50674 Cologne, Germany;3. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany;4. IUF—Leibniz Research Institute for Environmental Medicine, Aufm Hennekamp 50, 40225 Düsseldorf, Germany;1. II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum – Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Hamburg, Germany;2. Centrum für Thrombose und Hämostase, Universitätsmedizin der Johannes-Gutenberg-Universität Mainz, Mainz, Germany;3. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States;4. Department of Cardiology, New York University School of Medicine, New York, NY, United States |
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| Abstract: | Protein disulfide isomerase (PDI), a principal endoplasmic reticulum resident oxidoreductase chaperone, is known to play a role in malignancies. This study aims to explore the molecular mechanism by which PDI regulates endoplasmic reticulum stress and the apoptosis signaling pathway in colorectal cancer (CRC). We determined the expression of PDI in CRC tissues and adjacent normal tissues. Gain- and loss- of function assays were conducted to evaluate the effects of PDI on oxidative stress, endoplasmic reticulum stress, and apoptosis in CRC cells, as reflected by hydrogen peroxide (H2O2) level and the expression of related proteins. PDI protein expression was upregulated in CRC tissues. Small molecule inhibitor of PDI or PDI knockdown reduced CRC cell viability and induced apoptosis. Overexpression of wild-type PDI augmented the viability of CRC cells and inhibited endoplasmic reticulum stress response and apoptosis. Small molecule inhibitor of PDI or PDI knockdown increased intracellular H2O2 level and activated apoptosis signaling pathway, which could be reversed by wild-type PDI restoration. Moreover, the catalytic active site of C-terminal of PDI was found to be indispensable for the regulatory effects of PDI on H2O2 levels, apoptosis and cell viability in CRC cells. Collectively, PDI inhibits endoplasmic reticulum stress and apoptosis of CRC cells through its oxidoreductase activity, thereby promoting the malignancy of CRC. |
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