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Mitoxantrone triggers immunogenic prostate cancer cell death via p53-dependent PERK expression
Changlin Li1,2, Hui Sun3, Wei Wei4
1Institute of Precision Medicine, Jining Medical University, Jining, 272067, China. changlinli@mail.jnmc.edu.cn.
Background:
Mitoxantrone (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.
Methods:
ICD 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.
Results:
MTX 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.
Conclusion:
MTX 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.
Insights
Mitoxantrone triggers immunogenic cell death in prostate cancer by activating eIF2α through PERK and GCN2. This mechanism, particularly PERK upregulation via p53, enhances anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Mitoxantrone (MTX) is a chemotherapy agent for prostate cancer.
- MTX is known to induce immunogenic cell death (ICD) in preclinical models.
- The precise mechanism of MTX-induced ICD in prostate cancer cells remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which Mitoxantrone (MTX) induces immunogenic cell death (ICD) in prostate cancer cells.
- To investigate the role of PERK and GCN2 pathways in MTX-mediated ICD.
- To assess the impact of MTX on anti-tumor immunity in vivo.
Main Methods:
- Assessed damage-associated molecular patterns (DAMPs) release in prostate cancer cell lines (LNCaP, 22RV1, PC-3).
- Utilized short hairpin RNAs (shRNAs) for gene silencing (PERK, GCN2).
- Evaluated phagocytosis by dendritic cells and performed in vivo vaccination experiments in mice.
Main Results:
- MTX induced DAMP release (calreticulin, ATP, HMGB1) and enhanced dendritic cell phagocytosis.
- MTX increased eIF2α phosphorylation, dependent on PERK and GCN2.
- Silencing PERK or GCN2 reduced MTX-induced DAMP release and in vivo anti-tumor immunity.
Conclusions:
- MTX triggers ICD in prostate cancer cells by upregulating PERK and GCN2, leading to eIF2α activation.
- MTX-induced PERK upregulation is p53-dependent.
- The mechanism of GCN2 upregulation by MTX warrants further investigation.
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