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Data for p53 mutation in prostate cancer in The Cancer Genome Atlas database revealed that >85% of p53 mutations occurred in the p53 DNA binding domain. These mutations not only severely damage the function of the p53 protein, but also reduce the disease‑free survival of patients. Peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) is involved in the regulation of mitochondrial function and is highly expressed in prostate cancer PC3 and DU145 cells with p53 deletion or mutation. However, whether p53 negatively regulates PGC‑1α in prostate cancer cells remains to be elucidated. In the present study, p53 overexpression was induced in prostate cancer PC3 cells. Subsequently, the expression levels of PGC‑1α and alterations to mitochondrial function were assessed. Moreover, PGC‑1α was activated in prostate cancer PC3 cells using ZLN005 to investigate alterations to mitochondrial function and cell apoptosis. The present study revealed that p53 decreased the expression and nuclear localization of the PGC‑1α protein and induced mitochondrial dysfunction. Activation of PGC‑1α partially reversed p53‑mediated mitochondrial dysfunction. Inhibition of the p53/PGC‑1α pathway on mitochondrial biogenesis and fission‑/fusion‑associated gene and protein expression were associated with mitochondrial dysfunction. p53/PGC‑1α‑mediated mitochondrial dysfunction promoted apoptosis of PC3 prostate cancer cells. The results indicated that PGC‑1α is an essential target of p53‑induced apoptosis in prostate cancer cells and indicated that targeting PGC‑1α may provide a new therapeutic strategy for prostate cancer.

The main challenge for immune checkpoint blockade (ICB) therapy lies in immunosuppressive tumor microenvironment (TME). Repolarizing M2‐like tumor‐associated macrophages (TAMs) into inflammatory M1 phenotype is a promising strategy for cancer immunotherapy. Here, this study shows that the tumor suppressive protein SHISA3 regulates the antitumor functions of TAMs. Local delivery of mRNA encoding Shisa3 enables cancer immunotherapy by reprogramming TAMs toward an antitumoral phenotype, thus enhancing the efficacy of programmed cell death 1 (PD‐1) antibody. Enforced expression of Shisa3 in TAMs increases their phagocytosis and antigen presentation abilities and promotes CD8+ T cell‐mediated antitumor immunity. The expression of SHISA3 is induced by damage/pathogen‐associated molecular patterns (DAMPs/PAMPs) in macrophages via nuclear factor‐κB (NF‐κB) transcription factors. Reciprocally, SHISA3 forms a complex with heat shock protein family A member 8 (HSPA8) to activate NF‐κB signaling thus maintaining M1 polarization of macrophages. Knockout Shisa3 largely abolishes the antitumor efficacy of combination immunotherapy with Toll‐like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and PD‐1 antibody. It further found that higher expression of SHISA3 in antitumoral TAMs is associated with better overall survival in lung cancer patients. Taken together, the findings describe the role of SHISA3 in reprogramming TAMs that ameliorate cancer immunotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • UBE4B overexpression inhibits the apoptosis of SH-SY5Y cells via the AKT pathway. • Syringaresinol promotes the repair of spinal cord injury in rats via UBE4B overexpression, increases AKT phosphorylation, and reduces neuronal apoptosis. Spinal cord injury (SCI) is a serious traumatic disease with no effective treatment. This study aimed to explore the therapeutic effect of syringaresinol on SCI. First, the potential targets and associated signaling pathways of syringaresinol were predicted by bioinformatics analysis and molecular docking. Second, MTT was employed to evaluate cell proliferation rate, Western blot was performed to detect protein expression, RT-qPCR was conducted to detect mRNA expression levels, flow cytometry and 5-ethynyl-2′-deoxyuridine (EDU) staining were used to determine cell apoptosis, and immunofluorescence and immunohistochemistry were used to estimate the expression of RNA binding fox-1 homolog 3 and clipped caspase 3. Basso–Beattie–Bresnahan scores and inclined plate tests were conducted to analyze hindlimb locomotor function. Results showed that syringaresinol could inhibit the apoptosis of glutamate-treated SHSY5Y cells by upregulating the expression of ubiquitination factor E4B (UBE4B) and activating the AKT serine/threonine kinase (AKT) signaling pathway. This effect can be rescued by UBE4B knockdown or AKT pathway inhibition. Syringaresinol remarkably improved locomotor function and increased neuronal survival in SCI rats. Our results suggested that syringaresinol could promote locomotor functional recovery by reducing neuronal apoptosis by activating the UBE4B/AKT signaling pathway. [ABSTRACT FROM AUTHOR]