Therapy-induced senescence (TIS) may accelerate the progression of RB1-deficient castration-resistant prostate cancer (CRPC), driving metastasis and resistance to treatment.
RB1 expression is negatively correlated with malignancy in clinical prostate cancer samples.
maintained its efficacy in both RB1-knockdown and control groups in mouse models.
In RB1-deficient models, DIS was associated with increased metastasis and a transition to neuroendocrine prostate cancer (NEPC).
Elevated levels of senescence-associated β-galactosidase activity and p27 were observed in shRB1-DIS.
RNA sequencing identified a (SASP) in shRB1-DIS, featuring factors such as IL-1α, CCL5, and IL-20.
The senolytic agent ABT-263 reduced markers of shRB1-DIS and tumorigenic SASPs, enhancing sensitivity to docetaxel.
Simplified
UNLABELLED: PURPOSE RETINOBLASTOMA L: (RB1) mutations frequently emerge as late subclonal events in advanced prostate cancer (PCa), driving inevitable recurrence and therapy resistance. Therapy-induced senescence (TIS) could promote metastasis at a late stage. However, the underlying mechanisms and therapeutic approaches for decetaxel-induced senescence () in RB1-deficient castration-resistant prostate cancer (CRPC) remain poorly understood.
METHODS: We systematically evaluated the association between RB1 expression and tumor malignancy using TCGA-PRAD data and clinical prostate cancer samples. Multiple CRPC models were established, including RM-1 C57BL/6 and PC-3 BALB/c-nu mouse models, as well as human PC-3 and 22RV1 cells to uncover the double-edged nature of DIS. Subsequently, RNA sequencing of shRB1-DIS identified tumorigenic factors. Furthermore, we investigated the molecular mechanisms of the combined treatment using techniques such as immunofluorescence, flow cytometry, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and molecular docking.
RESULTS: The clinical significance and negative correlation between RB1 expression and malignancy were verified in human PCa samples. Using murine and human CRPC models, we demonstrated that DIS response was retained in both RB1-knockdown and control groups. Strikingly, DIS promoted metastasis and accelerated the transition to neuroendocrine prostate cancer (NEPC) in RB1-deficient models. shRB1-DIS was marked by elevated senescence-associated β-galactosidase (SA-β-gal) activity and upregulation of p27. RNA-seq analysis revealed a senescence-associated secretory phenotype (SASP) profile of shRB1-DIS, with upregulated IL-1α, CCL5, CCL20, MMP3, and IL-20. Mechanistically, we identified a novel FOXA1-IL20-IL20Rβ signaling axis which promoted macrophage polarization to M2-like phenotype. Notably, our data revealed that administration of ABT-263, eliminated shRB1 DIS-associated markers and SASPs, particularly, IL-20, both in vitro and in vivo experiments. Furthermore, molecular docking confirmed ABT-263 could directly bond to the IL-20 pocket with high affinity, and oeIL-20 advanced CRPC cells exhibited increased sensitivity to ABT-263 treatment. Therefore, the suppression of M2-like macrophages by ABT-263 was associated with reduced aggressiveness and decreased resistance to docetaxel in RB1-deficient CRPC. Kip
CONCLUSION: DIS accelerates the malignant progression of shRB1 CRPC, mediated by tumorigenic SASP, especially IL-20 enrichment. Notably, we identifies a novel FOXA1-IL-20-IL20Rβ axis that drives M2-like macrophage polarization and contributes to tumor aggressiveness and docetaxel resistance. Importantly, senolytic agent ABT-263 not only selectively eliminated shRB1-DIS cells but also restricted expression of tumorigenic SASPs, thereby restoring sensitivity to docetaxel. Wherein, IL-20 is inhibited through its interaction with ABT-263. These results provide a novel mechanistic rationale for using senolytic therapies to mitigate SASP-driven malignancy and improve treatment response in RB1-deficient CRPC.
CLINICAL TRIAL NUMBER: Not applicable.
Key numbers
1.67-fold
Tumor Volume Increase
Tumors from RB1-deficient mice were larger compared to control.
2.12-fold
M2 Macrophage Increase
M2-type macrophages increased significantly in docetaxel-treated mice.
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