Interaction between c-jun and Androgen Receptor Determines the Outcome of Taxane Therapy in Castration Resistant Prostate Cancer

Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients

Multivariate Analysis of the Failure of Removal of the Urinary Catheter within 48 Hours after Transurethral Enucleation and Resection of the Prostate

Objective. To assess the value of clinically relevant data for predicting the failure of removal of the urinary catheter within 48 hours after TUERP. Materials and Methods. We retrospectively analyzed the medical records of 357 patients who underwent TUERP between January 2015 and July 2018, all of whom stopped bladder irrigation and removed urinary catheter within 48 hours after the operation. According to whether the removal of the catheter was successful, the patients were classified into 2 groups: Group A was successful and group B was a failure. Univariate analysis was performed to determine the association between the failure of removal of the catheter and the patients’ preoperative clinical characteristics. Logistic regression analysis and receiver operating characteristic analysis (ROC) were conducted to establish the prediction model. Then the area under the curve (AUC) and the cut-off value were calculated. Results. 357 patients were divided into group A (n = 305, 85.4%) and group B (n = 52, 14.6%). The patients’ drug medication (P=0.006), history of acute urinary retention (AUR) (P≤0.001), smoke (P=0.045), IPSS (P≤0.001), IPP (P=0.006), PSA (P=0.047), residual urine volume (P≤0.001), QoL (P≤0.001), and TPV (P=0.043) were significantly different between the 2 groups. A predictive model using logistic regression was defined as follows: INDEX = 10.862–1.376 × (IPSS) − 1.185 × (QoL) − 1.062 × (drug medication) + 1.079 × (history of AUR) + 0.030 × (TPV) − 0.867 × (IPP) with area under the curve of 0.860 obtained from the ROC curve analysis. The predictive model had a cut-off value of 1.7725, and the sensitivity for predicting the failure of removal of the urethra was 74.1% and the specificity was 84.6%. Conclusion. This study demonstrated that IPSS, QoL, drug medication, history of AUR, TPV, and IPP are independent factors associated with the failure of removal of the urethral catheter within 48 hours after TUERP

Correction: Interaction between c-jun and Androgen Receptor Determines the Outcome of Taxane Therapy in Castration Resistant Prostate Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0079573.]

Bipolar transurethral enucleation and resection of the prostate: Whether it is ready to supersede TURP?

Objective: According to the EAU Guidelines, transurethral resection of the prostate (TURP) has so far still been considered as the gold standard for surgical treatment for patients with obstructing clinical benign prostate hyperplasia (BPH). However, its relatively high rate of complications and postoperative recurrence necessitates further modification and innovation on the surgery technique. We reported the patient outcomes with our technique. Methods: We retrospectively analyzed 52 patients with obstructing clinical BPH who underwent bipolar transurethral enucleation and resection of the prostate (B-TUERP) between March 2015 and September 2015. Pre- and perioperative parameters were obtained from medical charts. Postoperative follow-ups were administrated at 1, 3, 6, 12 and 24 month(s) after surgery, respectively. Results: All the operations were performed successfully with a mean operative time of 43.1 min and an average tissue removal rate of 74.7%. Qmax was significantly improved immediately after surgery, followed by a continuous improvement throughout the follow-ups. Following a steep decrease in mean prostate specific antigen (PSA) and post void residual (PVR) observed within the first half year after surgery, the serum PSA was then maintained at a constant level of 0.61 ng/mL. Temporary urinary retention was found in four cases (7.7%). Stress urinary incontinence occurred in five patients (9.6%), with the condition resolved in 1–2 weeks without extra treatment. Urethral strictures and bladder neck contractures, as the most commonly observed long-term complications, developed in four patients (7.7%). No recurrence was found during 2 years of follow-ups. An improvement in International Index of Erectile Function (IIEF-5) scores was witnessed in 17 patients preoperatively with normal sexual function during the first 6 months after surgery, and sustained throughout the 24-month period. Conclusions: Enucleation reflects an improvement on surgical technique in many ways with a need for surgical equipment that can be broadly accessible in clinical practice. Currently, bipolar resection is a commonly employed procedure in clinical settings, and its similarity shared with bipolar enucleation technique warrants a quick learning of B-TUERP by urologists. Based on these findings, we believe that the substitution of TURP by TUERP as the gold standard for prostate endoscopic procedure can be expected in the future

Tumor growth graphs and immunohistochemical analysis of dissected tumors from NMRI-nude mice bearing implanted LNCaP cells.

<p>(A) Growth curve of mice treated with Doc or Pac alone, Doc vs ctr (p=0.04). (B) Corresponding immunohistochemical staining of tumor tissue. (C) Growth curve of mice with combined treatment, Doc/bicalutamide (Bic) vs Pac/Bic (p=0.003). (D) Corresponding immunohistochemical staining of tumor tissue. Note that p-cjun was differentially expressed in mice treated with Doc and Pac. Ki67 expression was higher in Pac compared to Doc treated mice. </p

Determination of c-jun siRNA.

<p>(A) Western blotting analysis showing transfection efficiency of siRNA c-jun in both PC-3 and LNCaP cells. (B) Cell proliferation in LNCaP (upper panel) and PC-3 (lower panel) cells transfected with c-jun siRNA or nontargeted (control) vector. Cells were treated with Doc for 24 and 48 hours. LNCaP cells harbor c-jun siRNA showed a significant decrease in proliferation (p=0.002) while PC-3 cells were not affected. </p

Quantitative real-time RT-PCR.

<p>Expression of (A) AR and PSA and (B) c-jun, KLK2, NKX3.1 and c-Myc mRNA levels in response to Doc or Pac was evaluated by quantitative real time PCR (qPCR). The relative mean mRNA expression level of AR regulated genes was measured by quantitative real-time RT-PCR in triplicates. </p

Taxane-induced p-cjun expression is independent on JNK.

<p>Western blotting analysis of (A) PC-3 and (B) LNCaP cells exposed to Doc (5 nM) for up to 24 hours or remained untreated (0). PC-3 and LNCap cells were seeded in 24-well plates at a density of 50,000 cells per well and treated with Doc and Pac or in combination with 500 nM of JNK inhibitor (SB) as indicated. </p

Taxane altered AR, PSA and p-cjun protein level.

<p>Western blotting analysis of the expression of AR and PSA in (A) LNCaP and (B) LNb4 cells. Cells exposed to 5 nM of Doc, 5 nM of Pac or 10 nM of DHT for up to 48 hours or remained untreated. The same lysates were used to analyse the expression of p-cjun and c-jun in (C) LNCaP and (D) LNb4 cells. Protein expression levels were evaluated by densitometric analysis (lower panels).</p