FBXW2 is a poorly characterized F-box protein, as a tumor suppressor that inhibits growth and metastasis of lung cancer by promoting ubiquitylation and degradation of oncogenic proteins, including SKP2 and β-catenin. However, what the biological functions of FBXW2 in prostate cancer cells and whether FBXW2 targets other substrates to involve in progression of prostate cancer is still unclear. Here, we reported that overexpression of FBXW2 attenuated proliferation and metastasis of PCa models both in vitro and in vivo, while FBXW2 depletion exhibited the opposite effects. Intriguingly, FBXW2 was an E3 ligase for EGFR in prostate cancer. EGFR protein level and its half-life were extended by FBXW2 depletion, while EGFR protein level was decreased, and its half-life was shortened upon overexpression of FBXW2, but not its dominant-negative mutant. Importantly, FBXW2 bond to EGFR via its consensus degron motif (TSNNST), and ubiquitylated and degraded EGFR, resulting in repression of EGF function. Thus, our data uncover a novel that FBXW2 as a tumor suppressor of prostate cancer, inhibits EGFR downstream by promoting EGFR ubiquitination and degradation, resulting in repression of cell proliferation and metastasis.

Prostate cancer is the second leading cause of cancer-related death in men. Early prostate cancer has a high 5-year survival rate. However, the five-year survival rate is low in progressive prostate cancer, which manifests as bone metastasis. The EGF receptor overexpression increases during disease progression and in the development of castration-resistant disease, and may be a potential therapeutic target. Liver X receptors (LXRs) are ligand-dependent nuclear receptor transcription factors and consist of two subtypes, LXR-α and LXR-β, which can inhibit tumor growth in various cancer cells. We revealed that LXR-α, but not LXR-β, was reduced in prostate cancer tissues compared with adjacent normal tissues. LXRs’ agonist GW3965 enhanced the inhibitory action of LXR-α on the proliferation and metastasis of prostate cancer cells. Furthermore, our results support the notion that LXR-α is regulated by the EGFR/AKT/FOXO3A pathway. As an EGFR inhibitor, Afatinib could weaken AKT activation and increase the expression level of FOXO3A in prostate cancer. In addition, we indicated that the combination of Afatinib and GW3965 simultaneously increased and activated LXR-α, which led to an increase of tumor suppressors, and eventually inhibited tumor progression. Therefore, the combination of EGFR inhibitor and LXRs agonist may become a potential treatment strategy for prostate cancer, especially metastatic prostate cancer.

Background: The diagnostic value of prostate cancer antigen-3 (PCA3) in urine sediment and exosome in Chinese patients with total prostate specific antigen (PSA) ranging from 4-10ng/ml.Methods: Serum and urine samples were collected from consecutive eligible patients. The PCA3 and PSA mRNA were tested by quantitative real-time PCR. Results: Overall 130 patients were involved in this study. 113 cases in urinary sediments group and 103 cases in urinary exosomes group were finally analyzed. 24 of 130 patients (18.5%), 20 of 113 patients (17.7%) and 17 of 103 patients (16.5%) were diagnosed as PCa in the three groups, respectively. The PCA3 score and PSAD of patients with positive biopsy results were significantly higher than those with negative biopsy results in both the urinary sediments and exosomes groups, but no differences between two urinary substrates groups. The ROC analysis showed the higher values of AUC of the PCA3 score in urinary sediments and exosomes than that of serum PSA (0.728 vs 0.540, P = 0.0402; 0.740 vs 0.540, P = 0.0263), but no significant difference in term of AUC of PCA3 between two urinary substrates groups (0.728 vs 0.740, P = 0.9000), as well as when compared the AUC of the PCA3 score with that of %fPSA and PSAD (P > 0.05).Conclusion: The current evidence suggests that diagnostic performances of PCA3 in urinary sediments and exosomes were not significant different, but both were superior to serum PSA in Chinese patients with PSA 4–10ng/ml.

Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-refractory phenotype of advanced prostate cancer. This narrative review was informed by targeted searches of PubMed, Web of Science through May 2026. We classify evidence as Level A (human NEPC samples or clinical cohorts), Level B (NEPC-specific models), Level C (prostate adenocarcinoma or CRPC without NEPC resolution), or Level D (pan-cancer or non-prostate extrapolation), and apply these levels to central claims and a study-level evidence table. Direct human data support immune depletion in most NEPC tumors, with heterogeneous macrophage, fibroblast and lymphoid remodeling in selected cohorts; model studies support context-dependent cytokine, hypoxic, extracellular-matrix and metabolic effects on lineage plasticity. By contrast, CAF-derived lactate fueling NEPC, a dense collagen drug barrier, and NEPC-specific vascular permeability remain unvalidated. Most TME-directed treatments are preclinical or extrapolated, whereas DLL3-directed therapy has shown early activity in biomarker-selected disease. Longitudinal biopsies, spatial multi-omics, humanized models and biomarker-defined trials are needed to distinguish causal vulnerabilities from correlates of treatment-emergent lineage transition.