Abstract 5655: Brefeldin A mediates integrated stress response and in combination with Navitoclax induces apoptosis in prostate cancer cells

Abstract

Abstract Introduction and Objectives: Metastatic castration resistance prostate cancer is a lethal disease. New AR-axis-targeted agent are available, but they will eventually become ineffective. Brefeldin A, an endoplasmic reticulum (ER) protein transport inhibitor, has been shown to cause ER stress. Navitoclax is a BH3 mimetic drug that targets anti-apoptotic proteins (BCL2 and BCLXL) and induces apoptosis in some solid tumors. Here, we investigated the efficacy of Brefeldin A combined with navitoclax on prostate cancer cells. Materials and Methods: We assessed the effect of combination therapy for prostate cancer cells using MTS assay, qRT-PCR, luciferase assay, and western blot. Results: Combination therapy with Brefeldin A and navitoclax synergistically decreased cell viability in prostate cancer cells. Mechanistically, Brefeldin A induced MCL1 degradation and, combined with navitoclax, drove apoptosis. Further, integrated stress response was at least in part involved in Brefeldin A-induced MCL1 degradation. Conclusions: Combination therapy with Brefeldin A and navitoclax shows synergistic anti-tumor effects in prostate cancer cells. These results suggest that Brefeldin A might still be effective in prostate cancer if used with navitoclax. Citation Format: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki. Brefeldin A mediates integrated stress response and in combination with Navitoclax induces apoptosis in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5655.