大島 将

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4K), also known as type II PIPKs or PIPKIIs, convert the lipid second messenger PI5P to PI(4,5)P2. The PI5P4K family consists of three isozymes in mammals-PI5P4Kα, β, and γ-which notably utilize both GTP and ATP as phosphodonors. Unlike the other two isozymes, which can utilize both ATP and GTP, PI5P4Kβ exhibits a marked preference for GTP over ATP, acting as an intracellular GTP sensor that alters its kinase activity in response to physiological changes in GTP concentration. Knockout studies have demonstrated a critical role for PI5P4Kα and β in tumorigenesis, while PI5P4Kγ has been implicated in regulating immune and neural systems. Pharmacological targeting of PI5P4K holds promise for the development of new therapeutic approaches against cancer, immune dysfunction, and neurodegenerative diseases. Although several PI5P4K inhibitors have already been developed, challenges remain in PI5P4K inhibitor development, including a discrepancy between in vitro and cellular efficacy. This discrepancy is attributable to mainly three factors. (a) Most PI5P4K inhibitors were developed at low ATP levels, where these enzymes exhibit minimal activity. (b) Non-catalytic functions of PI5P4K require careful interpretation of PI5P4K depletion studies, as their scaffolding roles suppress class I PI3K signaling. (c) The lack of pharmacodynamic markers for in vivo assessment complicates efficacy assessment. To address these issues and promote the development of effective and targeted therapeutic strategies, this review provides an analytical overview of the distinct roles of individual isozymes and recent developments in PI5P4K inhibitors, emphasizing structural insights and the importance of pharmacodynamic marker identification.

This study aimed to identify the predictive factors associated with the oncological outcomes of metastatic hormone-sensitive prostate cancer-related genes. A nomogram for predicting prostate cancer-specific survival (CSS) was constructed based on biopsy samples obtained from 103 patients with metastatic hormone-sensitive prostate cancer. We analyzed the association between clinical data and mRNA expression levels. The nomogram was externally validated in another cohort (n = 50) by using a concordance index. Based on the cutoff value, determined by a receiver operating characteristic analysis, longer CSS was observed in the high osteoglycin and androgen receptor expression level groups (> 1.133 and > 0.00; median CSS, 85.3 vs. 52.7 months, p = 0.045, and 69.1 vs. 32.1 months, p = 0.034, respectively), compared with that of the low expression level groups. The nomogram predicting CSS included hemoglobin (≥ 13.7 g/dL or < 13.7 g/dL), serum albumin (≥ 3.1 g/dL or < 3.1 g/dL), serum lactate dehydrogenase (≥ 222 IU/L or < 222 IU/L), total Japan Cancer of the Prostate Risk Assessment score, androgen receptor expression level, and osteoglycin expression level. The concordance indices for the internal and external validations were 0.664 and 0.798, respectively. In this study, a nomogram that integrated the expression levels of androgen receptors and osteoglycin to predict CSS in metastatic hormone-sensitive prostate cancer was established.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) is a preferred minimally invasive surgical treatment for prostate cancer. The number of elderly patients and those with cardiovascular and/or cerebrovascular issues undergoing surgery is increasing, and many of them are taking antithrombotic (AT) agents. However, the effect of AT agents on postoperative urinary recovery has not been adequately studied. In this study, we analyzed the differences in the postoperative recovery of urinary continence and oncological outcomes in patients undergoing RARP for localized prostate cancer between AT agent adherents and non-adherents. METHODS: A total of 394 patients who underwent conventional anterior RARP between February 2015 and February 2021 were categorized into two groups: those taking oral AT agents (AT group) and the control group. Urinary continence recovery, complications, and oncological outcomes were compared between the groups. A Cox proportional hazards analysis was performed to identify clinical factors that affect urinary continence recovery. RESULTS: The background data and bleeding complications did not differ significantly between the groups. The recovery of continence was significantly poorer in the AT group in terms of complete pad free (HR: 0.53 [95% CI: 0.39-0.71]) and use of ≤ 1 safety pad (HR: 0.74 [95% CI: 0.59-0.94]). The rate of anastomotic leakage on cystography was significantly higher in the AT group (20.9% vs. 6.7%). A univariate analysis revealed that taking antithrombotic agents, higher prostate-specific antigen levels, and a more advanced clinical stage were associated with a poor urinary continence recovery; a multivariate analysis showed that taking AT agents was an independent factor negatively associated with urinary continence recovery. There was no significant difference between the groups in the positive surgical margin rate (19.0% vs. 23.8%) or the biochemical-recurrence-free rate. CONCLUSION: Taking oral AT agents may be associated with poor urinary continence recovery after RARP.

Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{cis-Pt(NH3)2}2(μ-OH)(μ-azolato)]X2, where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling. Therefore, here we investigated the potential of 14 such complexes as agents for the treatment of prostate cancer by examining their antiproliferative activity in the human prostate adenocarcinoma cell line LNCaP. Several of the complexes, particularly 5-H-Y ([{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)](ClO4)2), effectively inhibited LNCaP cell growth, even at low concentrations, by direct modulation of AR signaling, and by binding to DNA and inducing apoptosis, which is a common mechanism of action of Pt-based drugs such as cisplatin (cis-diamminedichloridoplatinum(II)). Comparative analysis with cisplatin revealed superior inhibitory effects of these complexes. Further investigation revealed that 5-H-Y suppressed mRNA expression of genes downstream from AR and induced apoptosis, particularly in cells overexpressing AR, highlighting its potential as an AR antagonist. Thus, we provide here insights into the mechanisms underlying the antiproliferative effects of azolato-bridged complexes in prostate cancer.

Although hormone therapy is effective for the treatment of prostate cancer (Pca), many patients develop a lethal type of Pca called castration-resistant prostate cancer (CRPC). Dysregulation of DNA damage response (DDR)-related genes leads to Pca progression. Here, we explored DDR-related signals upregulated in CRPC tissues. We analyzed the gene expression profiles in our RNA-sequence (RNA-seq) dataset containing benign prostate, primary Pca, and CRPC samples. We identified six DDR-related genes (Ribonuclease H2 Subunit A (RNASEH2A), replication factor C subunit 2 (RFC2), RFC4, DNA Ligase 1 (LIG1), DNA polymerase D1 (POLD1), and DNA polymerase E4 (POLE4)) that were upregulated in CRPC compared with Pca tissues. By analyzing public databases and validation studies, we focused on RFC2 as a new biomarker. Functional analysis demonstrated that silencing of RFC2 expression inhibited cell proliferation and induced the expression of DNA damage and apoptosis markers in CRPC model cells. Furthermore, immunohistochemical (IHC) analysis revealed that high expression of RFC2 protein correlated with poor prognosis in patients with Pca and increased expression in CRPC tissues compared with localized Pca. Thus, our study suggests that six DDR-related genes would be important for Pca progression. RFC2 could be a useful biomarker associated with poor outcomes of patients with Pca.