Metabolic reprogramming and cellular senescence greatly contribute to cancer relapse and recurrence. In aging and treated prostate, persistent accumulating senescence-associated secretory phenotype (SASP) of cancer cells often limits the overall survival of patients. Novel strategic therapy with monoacylglycerol lipase (MGLL) upregulation that counters the cellular and docetaxel induced SASP might overcome this clinical challenge in prostate cancer (PCa). With primary comparative expression and survival analysis screening of fatty acid (FA) metabolism signature genes in the TCGA PCa dataset and our single center cohort, MGLL was detected to be downregulated in malignancy prostate tissues and its low expression predicted worse progression-free and overall survival. Functionally, overexpression of MGLL mainly suppresses NF-κB-driven SASP (N-SASP) which mostly restricts the cancer cell paracrine and autocrine tumorigenic manners and the corresponding cellular senescence. Further investigating metabolites, we determined that MGLL constitutive expression prevents lipid accumulation, decreases metabolites preferably, and consequently downregulates ATP levels. Overexpressed MGLL inhibited IκBα phosphorylation, NF-κB p65 phosphorylation, and NF-κB nuclear translocation to deactivate NF-κB transcriptional activities, and be responsible for the repressed N-SASP, partially through reducing ATP levels. Preclinically, combinational treatment with MGLL overexpression and docetaxel chemotherapy dramatically delays tumor progression in mouse models. Taken together, our findings identify MGLL as a switch for lipase-related N-SASP suppression and provide a potential drug candidate for promoting docetaxel efficacy in PCa.

Supplemental figure 1 ASC-J9® degraded androgen receptor expression in bladder cancer

Supplemental figure 2 HF or ASC-J9® induced THP-1 cell differentiating to M1 macrophage

Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette-Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.

Epithelial-mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.

Abstract Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette–Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5β1 expression and IL6 release. Such consequences might then enhance BCG-induced bladder cancer cell death via increased TNFα release. Interestingly, we also found that ASC-J9 treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for suppression of bladder cancer cell growth. In vivo approaches also concluded that ASC-J9 could enhance the efficacy of BCG to better suppress bladder cancer progression in BBN-induced bladder cancer mouse models. Together, these results suggest that the newly developed therapy combining BCG plus ASC-J9 may become a novel therapy to better suppress bladder cancer progress. Mol Cancer Ther; 14(11); 2586–94. ©2015 AACR.

Transforming growth factor-β1 (TGFβ1) plays a significant role in regulating cellular proliferation and apoptosis. A large number of studies related to the association between TGFβ1 Leu10Pro polymorphism and prostate cancer (PC) risk, but get conflicting results. We performed a meta-analysis based on six studies, assessing the strength of the association using odds ratios (OR) with 95 % confidence intervals (CI). Overall, our evidence has indicated that TGFβ1 Leu10Pro polymorphism had significantly increased PC risk in the allele comparison model (OR = 1.081, 95 % CI = 1.003–1.165, P heterogeneity = 0.141, P = 0.041). In the stratified analysis by ethnicity, the same results were found among Caucasians (for heterozygote model, OR = 1.741, 95 % CI = 1.004–3.020, P heterogeneity = 0.000, P = 0.049; recessive model, OR = 1.339, 95 % CI = 1.045–1.717, P heterogeneity = 0.020, P = 0.021; allele comparison model, OR = 1.091, 95 % CI = 1.005–1.184, P heterogeneity = 0.048, P = 0.037). In conclusion, this meta-analysis suggested that TGFβ1 Leu10Pro polymorphism contributed to the development of PC. A well-designed and larger study is still required to evaluate this polymorphism and PC risk.

Objective:To explore the diagnosis and treatment of penile verrucous carcinoma.Methods:The clinical and pathological data of 5 patients with penile verrucous carcinoma were analyzed with literature review to discuss its etiology and pathology,characteristics,diagnosis and treatment from January 2007 to January 2012.Results:None of 5 patients received ilioinguinal lymphadenectomy.Histopathological examination of the specimens showed that the tumor cells were mostly well-differentiated and the surgical margins were tumor free in all the 5 cases.HE stain was performed in all the specimens.Microscopic examination revealed papillomatosis and hyperkeratosis of the epithelium,with bulbous projections into the lamina propria consisting of well-differentiated squamous epithelial cells.Marked invasion of the stroma by lymphocytes was noted.Follow-up ranged from 0.6 to 5 years(average 3.4),revealing no recurrence.The patients with local excision of the tumors reported satisfaction of their sexual lives.Conclusions:Verrucous carcinoma of the penis is a well-differential disease with low malignant potential and locally aggressive nature.It seldom develops metastasis to regional lymphonodes or distant areas. Glansectomy or partial penectomy can be chosen for its treatment,with favorable prognosis.When the disease could closely related with HPV infection,tumor recur easily by pure surgical treatment,so it is necessary to do the specific therapy and long-term follow-up.

Objective To explore the function and mechanism of estrogen receptor α (ERα) in bladder cancer cell proliferation and aggressivity.Methods The ERα expression bladder cancer cell line T24ERα model was established.The cell growth was detected by MTT assay,apoptosis by flow cytometry,cell invasion by matrigel transwell.Western blot was used to check signals by ERα regulation in bladder cancer cells related to the proliferation and metastatic ability.Results Compared to the control group,the cell inhibition rates of experimental group in 96 h and 144 h were 18.85％ and 37.21％,respectively.The difference was significant compared with the control group (P ＜ 0.05).The apoptosis rates of the experimental group and control group were (18.93 ±1.41)％ and (9.91 ±1.08)％ (P＜0.05).The experimental group through matrix adhesive cell proportion was (10.00 ± 2.00)％,significantly lower than that of the control group (26.00 ± 3.61) ％ (P ＜ 0.05).Western blot showed integrin-β1,p-FAK,p-Src and Scr expression were reduced compared to control group (P ＜ 0.05).Conclusion ERα could inhibit bladder cancer cell growth and metastasis through down-regulating integrin-β1-FAK/Src signal pathway,while promote the apoptosis of bladder cancer cells.