Impaired expression of connexins, the gap junction subunits that facilitate direct cell-cell communication, have been implicated in prostate cancer growth. To elucidate the crucial role of connexins in prostate cancer progression, we performed a systematic quantitative RT-PCR screening of connexin expression in four representative prostate cancer cell lines across the spectrum of malignancy. Transcripts of several connexin subunits were detected in all four cell lines, and connexin 43 (Cx43) showed marked elevation at both RNA and protein levels in cells with increased metastatic potential. Analysis of gap-junction-mediated intercellular communication revealed homocellular coupling in PC-3 cells, which had the highest Cx43 expression, with minimal coupling in LNCaP cells where Cx43 expression was very low. Treatment with the gap junction inhibitor carbenoxolone or connexin mimetic peptide ACT-1 did not impair cell growth, suggesting that growth is independent of functional gap junctions. PC-3 cells with Cx43 expression reduced by shRNA showed decreased migration in monolayer wound healing assay, as well as decreased transwell invasion capacities when compared to control cells expressing non-targeting shRNA. These results, together with the correlation between Cx43 expression levels and the metastatic capacity of the cell lines, suggest a role of Cx43 in prostate cancer invasion and metastasis.
Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development.
Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer.
Introduction: Many implanters have transitioned penile implantation procedures from 23-hour observation (OBS) stays to same-day discharge surgeries (SDS). Postoperative urinary retention (POUR) represents a potential barrier to successful SDS among in atable penile prosthesis (IPP) recipients; however, its incidence and resolution have not been well characterized. We rigorously characterized POUR in a cohort of IPP recipients along with risk factors and management.Materials and Methods: Patients undergoing IPP from 2014 through 2020 without pre-existing retention were included. All patients underwent void trial immediately following IPP in PACU. POUR was strictly de ned as: 1) any patient requiring catheter replacement after IPP, 2) a rising post-void residual (PVR), or 3) inability to void after 6 hours regardless of whether a catheter was placed. Independent demographic, intraoperative, and postoperative risk factors for POUR were assessed using multivariable logistic regression.Results: 317 men were included of whom 27.1% experienced POUR. Rates of POUR in patients under OBS or SDS were not signi cantly different (29.2% vs. 18.0%, p=0.11). Men experiencing POUR and those not in retention were essentially indistinguishable with respect to risk factors for POUR. Only maximal medical therapy for BPH was signi cantly associated with a greater risk of POUR, a nding maintained on adjusted analysis (aOR 10.1, 95% CI 2.1 to 49.8). POUR resolved without intervention in 3.5%, a single episode of CIC in 7.0% of patients, and repeated CIC or indwelling catheter placement with a successful delayed void trial in 88.4% of patients. Rate of IPP infection in patients who experienced POUR vs. N-POUR did not differ (4.7% vs. 2.2% p=0.26).Conclusion: POUR is experienced in as many as 1 in 4 men undergoing IPP placement, most of whom must be managed with indwelling catheterization or repeated CIC. Those with indicators of symptomatic BPH are at signi cantly greater risk of urinary retention.
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