Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

Abstract

// Ahmed Elhassanny 1 , Rene Escobedo 1 , Daniel Ladin 2 , Colin Burns 3 and Rukiyah Van Dross 1 , 3 , 4 1 Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA 2 Medical Doctor Program, Brody School of Medicine, East Carolina University, Greenville, NC, USA 3 Department of Chemistry, East Carolina University, Greenville, NC, USA 4 Center for Health Disparities, East Carolina University, Greenville, NC, USA Correspondence to: Rukiyah Van Dross, email: [email protected] Keywords: calreticulin; endoplasmic reticulum stress; dendritic cells; endocannabinoid metabolite Received: September 29, 2020     Accepted: December 16, 2020     Published: December 29, 2020 Copyright: © 2020 Elhassanny et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Metastatic melanoma is the most deadly skin neoplasm in the United States. Outcomes for this lethal disease have improved dramatically due to the use of both targeted and immunostimulatory drugs. Immunogenic cell death (ICD) has emerged as another approach for initiating antitumor immunity. ICD is triggered by tumor cells that display damage-associated molecular patterns (DAMPs). These DAMP molecules recruit and activate dendritic cells (DCs) that present tumor-specific antigens to T cells which eliminate neoplastic cells. Interestingly, the expression of DAMP molecules occurs in an endoplasmic reticulum (ER) stress-dependent manner. We have previously shown that ER stress was required for the cytotoxic activity of the endocannabinoid metabolite, 15-deoxy, Δ 12,14 prostamide J 2 (15dPMJ 2 ). As such, the current study investigates whether 15dPMJ 2 induces DAMP signaling in melanoma. In B16F10 cells, 15dPMJ 2 caused a significant increase in the cell surface expression of calreticulin (CRT), the release of ATP and the secretion of high-mobility group box 1 (HMGB1), three molecules that serve as surrogate markers of ICD. 15dPMJ 2 also stimulated the cell surface expression of the DAMP molecules, heat shock protein 70 (Hsp70) and Hsp90. In addition, the display of CRT and ATP was increased by 15dPMJ 2 to a greater extent in tumorigenic compared to non-tumorigenic melanocytes. Consistent with this finding, the activation of bone marrow-derived DCs was upregulated in co-cultures with 15dPMJ 2 -treated tumor compared to non-tumor melanocytes. Moreover, 15dPMJ 2 -mediated DAMP exposure and DC activation required the electrophilic cyclopentenone double bond within the structure of 15dPMJ 2 and the ER stress pathway. These results demonstrate that 15dPMJ 2 is a tumor-selective inducer of DAMP signaling in melanoma.

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