Proteasome inhibitors attenuates mitoxantrone-triggered immunogenic cell death in prostate cancer cells
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ORIGINAL PAPER
Proteasome inhibitors attenuates mitoxantrone‑triggered immunogenic cell death in prostate cancer cells Wei Wei1 · Haibin Li2 · Guoan Zhang3 · Ying Zhang2 · Ke Wu2 · Rongrong Bao2 · Gege Wang2 · Han Zheng2 · Yong Xia2 · Changlin Li2 Received: 17 October 2020 / Accepted: 14 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Both mitoxantrone (MTX) and proteasome inhibitors efficiently trigger immunogenic cell death (ICD) in cancer cells. However, whether the combination of MTX and proteasome inhibitors can synergistically enhance ICD remains unknown. In this study, we showed that the proteasome inhibitors bortezomib (BZM) and carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132) impaired MTX-induced ICD in prostate cancer cells, as measured using ICD biomarkers and dendritic cell activation in vitro. Mice vaccinated with RM-1 mouse prostate cancer cell line treated with BZM or MG132 in combination with MTX showed enhanced tumor growth, and shortened tumor-free, and worse overall survival compared with those treated with MTX alone. In conclusion, we demonstrated that proteasome inhibitors (BZM or MG132) attenuated MTX-induced ICD, suggesting that proteasome activation was required for MTX-induced ICD. Keywords Immunogenic cell death · Mitoxantrone · Bortezomib · Proteasome inhibitor
Introduction Recent studies have shown that cancer cell death can be induced by multiple stimuli, including chemotherapeutics, physical interventions (e.g., radiation, high hydrostatic pressure, and hypericin-based photodynamic therapy), and necroptosis, thereby triggering immune responses against the tumor, known as immunogenic cell death (ICD) [1–3]. During ICD, cells exhibit elevated secretion of damageassociated molecular patterns (DAMPs), including surface exposure of calreticulin (CALR), secretion of adenosine triphosphate (ATP), and release of high-mobility group box 1 (HMGB1). Subsequently, release of these DAMPs activates phagocytosis by dendritic cells (DCs), resulting in Wei Wei and Haibin Li have contributed equally to this work. * Changlin Li [email protected] 1
Center for Experimental Medicine, School of Public Health, Jining Medical University, Jining 272067, China
2
Institute of Precision Medicine, Jining Medical University, Jining 272067, China
3
Institute of Cancer Pathology Research, Jining Medical University, Jining 272067, China
engulfment of tumor antigens [4, 5] and ultimately activating antitumor immune responses [6]. The ubiquitin proteasome system (UPS) is essential for the maintenance of protein homeostasis by regulating selective degradation of proteins, and it is involved in many biological processes, including immune responses in eukaryotes. Disruption of the UPS has been linked to the development of multiple diseases, including cancers [7]. Previous studies have demonstrated that proteasome activity is elevated in several cancers, and proteasome targeting may be an important therapeutic strategy against cancers [8, 9]. The anti
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