ArticleCellular oncology (Dordrecht, Netherlands)2020
Mitoxantrone triggers immunogenic prostate cancer cell death via p53-dependent PERK expression.
Article in Cellular oncology (Dordrecht, Netherlands), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 63 citations in OpenAlex.
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- Viral mimicry may help explain immunogenic cell death.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Chromatin regulatorsChinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2026Article
- Integrated Bioinformatics and Experimental Validation Reveal Fuzheng Yi'ai Formula Induces Immunogenic Cell Death Via the PERK-eIF2α-ATF4 Pathway for Prostate Cancer Treatment.Biological procedures online · 2026Article
- TUB-040, a Homogeneous and Hydrophilic NaPi2b-Targeting ADC with Stably Linked Exatecan, Exhibits Long-lasting Antitumor Activity and a Well-Tolerated Safety Profile.Molecular cancer therapeutics · 2025Article
- Isolation of New Chemical Modulators of the Interaction Between HIV-1 Integrase and the Cellular Restriction Factor GCN2.Viruses · 2025Article
- Elucidating DNA Damage-Dependent Immune System Activation.International journal of molecular sciences · 2025Review
- Regulation of immunogenic cell death and potential applications in cancer therapy.Frontiers in immunology · 2025Review
- MiR-183-5p inhibitor promotes mitoxantrone-induced immunogenic death of hepatoma cells by targeting STC1.International journal of clinical and experimental pathology · 2025Article
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
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- Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer.Nature communications · 2024Article
- Injecting hope: the potential of intratumoral immunotherapy for locally advanced and metastatic cancer.Frontiers in immunology · 2024Review
- Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview.Frontiers in immunology · 2024Review
- Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death.Frontiers in pharmacology · 2024Article
- Tumor microenvironment-responsive micelles assembled from a prodrug of mitoxantrone and 1-methyl tryptophan for enhanced chemo-immunotherapy.Drug delivery · 2023Article
- Recent advances and future perspectives in the therapeutics of prostate cancer.Experimental hematology & oncology · 2023Article
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Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundMitoxantrone (MTX) is a synthetic compound used as a second line chemotherapeutic drug for prostate cancer. It has been reported to trigger immunogenic cell death (ICD) in animal model studies, but the underlying mechanism is not fully understood yet, especially not in prostate cancer cells.
methodsICD was determined by assessing the release of damage-associated molecular patterns (DAMPs) in the prostate cancer-derived cell lines LNCaP, 22RV1 and PC-3. Short hairpin RNAs (shRNAs) were used to knock down target gene expression. Phagocytosis was assessed using a dual labeling technology in dendric cells co-cultured with cancer cells. The PERK gene promoter was cloned for dual luciferase assays. Chromatin immunoprecipitation (ChIP) was used to determine p53 protein-DNA binding activity. Immunocompetent mice and murine RM-1 prostate cancer cells were used for vaccination experiments.
resultsMTX treatment induced typical characteristics of DAMP release, including increased cell surface exposure of calreticulin (CALR), and extracellular release of ATP and high mobility group box-1 (HMGB1) protein. MTX also enhanced phagocytosis by dendritic cells. Moreover, MTX treatment increased eukaryotic initiation factor 2α (eIF2α) S51 phosphorylation, which was reduced when PERK and GCN2 were silenced using shRNAs. In addition, PERK or GCN2 silencing significantly reduced MTX-induced release of DAMPs in vitro and anti-tumor immunity in vivo. MTX treatment also resulted in dendritic cell activation in mice, which was attenuated when PERK or GCN2 were silenced in cancer cells used for vaccination. Further analysis revealed that PERK and GCN2 expression was enhanced by MTX treatment, of which PERK, but not GCN2, was enhanced via a p53-dependent mechanism.
conclusionMTX triggers ICD by activating eIF2α via PERK/GCN2 upregulation in prostate cancer cells. MTX-induced PERK expression upregulation depends on the p53 pathway, while that of GCN2 requires further investigation.
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