ISSN: 1837-9664Journal of Cancer
Global reach, higher impact
J Cancer 2024; 15(7):1779-1785. doi:10.7150/jca.92252 This issue Cite
Research Paper
Inducing Melanoma Cell Apoptosis by ERp57/PDIA3 Antibody in the Presence of CPI-613 and Hydroxychloroquine
1. Department of Dermatology, Gifu University Graduate School of Medicine, Gifu, Japan.
2. Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan.
3. The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
4. Center for One Medicine Innovative Translational Research; COMIT, Gifu University, Gifu, Japan.
Abstract
The combination of the cancer mitochondrial metabolic inhibitor CPI-613 and hydroxychloroquine has tumor-suppressive effects on clear cell sarcoma, which shares pathobiological properties with melanoma. Therefore, we intended to examine the effects of a combination of CPI-613 and hydroxychloroquine on the growth of melanoma cells in the present study. However, cell death was not induced in melanoma cells. Therefore, a monoclonal antibody, ICT, that induced apoptosis in melanoma cells in combination with CPI-613 and hydroxychloroquine was developed. Immunoprecipitation, mass spectrometry, and small interfering RNA (siRNA)-mediated gene silencing demonstrated that ICT targeted Endoplasmic Reticulum Resident Protein 57/ Protein Disulfide Isomerase Family A Member 3 (ERp57/PDIA3), which was first identified as being upregulated by metabolic depletion stress and is localized on the cell surface during immunogenic cell death. The combination of CPI-613 and hydroxychloroquine enhanced the localization of ERp57/PDIA3 to the surface of melanoma cells. siRNA-mediated downregulation of ERp57/PDIA3 did not significantly induce ICT-mediated apoptosis in melanoma cells in the presence of CPI-613 and hydroxychloroquine. Therefore, the ICT antibody acts as a tumor suppressor in melanoma cells by targeting the cell membrane ERp57/PDIA3, expression of which was enhanced by the combination of CPI-613 and hydroxychloroquine.
Keywords: melanoma, CPI-613, ERp57/PDIA3, hydroxychloroquine, monoclonal antibody
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