Docetaxel is the first-line chemotherapy agent for metastatic prostate cancer. However, the emergence of resistance diminishes its efficacy and limits the survival benefit. Quercetin is a dietary flavonoid which has been shown to have multiple anti-cancer effects. Also, quercetin has been reported to reverse chemo-resistance in many other cancers. This study was to determine whether quercetin could reverse docetaxel resistance in prostate cancer cells and xenograft models, thereby exploring the underlying mechanism. Depending on the docetaxel-resistant cells (LNCaP/R, PC-3/R) which were established from docetaxel-sensitive cells (LNCaP, PC-3), it was demonstrated that quercetin could reverse docetaxel resistance in prostate cancer on proliferation, colony formation, migration, invasion and apoptosis. Although single docetaxel application had little effect on docetaxel-resistant cells, combining docetaxel with quercetin was significantly effective. Combination therapy could maximally inhibited PI3K/Akt pathway and promoted apoptosis. As shown by in-vivo study, xenograft tumors treated by docetaxel with quercetin had poorest growth. Then, to investigate the underlying mechanisms, the differences among parental cells, docetaxel-resistant subclones and quercetin treated resistant subclones were evaluated. It was found that docetaxel-resistant subclones had stronger activation of androgen receptor and PI3K/Akt pathway, more remarkable mesenchymal and stem-like cell phenotypes, and more P-gp expression than that of parental cells. Interestingly, quercetin could reverse these transformations. Our data revealed that quercetin had docetaxel-resistance reversal effect both in vitro and in vivo and provided in-depth support for clinical use of quercetin in docetaxel-resistant prostate cancer.

Background: Prostate cancer (PC) is one of the most common carcinomas in men worldwide. The lack of effective therapies urges the development of novel therapeutic options against PC. Quercetin (Quer) is a flavonoid compound that has been shown to effectively inhibit PC in vitro and in vivo. However, the underlying mechanisms await elucidation. Long non-coding RNA MALAT1 has been reported as an oncogenic target in multiple types of cancers, including PC. Previous data showed that quercetin promoted the apoptosis of fibroblast-like synoviocytes by upregulating MALAT1 in rheumatoid arthritis. However, we speculate that mechanisms are different in PC. Materials and Methods: Human PC cell line PC-3 and its xenograft tumor were chosen as in vitro and in vivo models for PC. A series of in vitro and in vivo functional experiments were carried out to elucidate the role of MALAT1 in quercetin treatment against PC. Western blot was performed to measure the expression of related proteins to explore underlying molecular mechanisms. Results: We showed for the first time that MALAT1 expression was significantly downregulated in quercetin-treated PC cells in a dose- and time-dependent manner. Also, quercetin inhibited the proliferation of PC cells and the growth of xenograft tumors. Moreover, quercetin suppressed EMT process, promoted apoptosis and deactivated PI3K/Akt signaling pathway during the progression of PC. MALAT1 overexpression in PC cells resulted in the resistance against quercetin treatment. Conclusion: Our study illustrated, for the first time, that MALAT1 played an important role in quercetin treatment against PC by inhibiting EMT process and promoting apoptosis, providing a new molecular basis for the application of quercetin in PC treatment.

Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conduct whole-genome and targeted sequencing in urothelial bladder carcinomas (UBCs, the most common type of bladder cancer). Recurrent mutations in noncoding regions affecting gene regulatory elements and structural variations (SVs) leading to gene disruptions are prevalent. Notably, we find recurrentADGRG6enhancer mutations andFRS2duplications which are associated with higher protein expression in the tumor and poor prognosis. Functional assays demonstrate that depletion ofADGRG6orFRS2expression in UBC cells compromise their abilities to recruit endothelial cells and induce tube formation. Moreover, pathway assessment reveals recurrent alterations in multiple angiogenesis-related genes. These results illustrate a multidimensional genomic landscape that highlights noncoding mutations and SVs in UBC tumorigenesis, and suggest ADGRG6 and FRS2 as novel pathological angiogenesis regulators that would facilitate vascular-targeted therapies for UBC.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is identified as a urinary andrological diseases that afflict men due to various discomforts. It is urgent and meaningful to develop the novel and effective treatments as a result of the unclear etiology and dismal therapeutic effect of CP/CPPS. Lycopene exerts a crucial role in numerous chronic inflammatory diseases owing to its potent antioxidant capacity.Objective: This study aimed to observe the effect of lycopene on CP/CPPS and to explore the underlying mechanisms.Materials and Methods: A CP/CPPS model with complete Freund's adjuvant was established in this study. Afterward, intragastric lycopene or corn oil was administered daily for 4 consecutive weeks. Finally, the cardiac blood and prostate tissue samples were collected from rats to carry out related evaluation and testing.Results: It was found in this study that lycopene alleviated changes in prostate histopathology compared with those in the complete Freund's adjuvant‐induced CP/CPPS model rats without lycopene treatment. Furthermore, lycopene was suggested to reduce the levels of chemokines MCP1 and MIP‐1α, down‐regulate the expression levels of cytokines (such as TNFα, IL‐1β, IL‐2, and IL‐6), and up‐regulate those of CAT, GSH‐PX, and T‐SOD, decrease that of malondialdehyde. Moreover, it also inhibited the phosphorylation of MAPKs, NF‐κB, and enhanced phosphorylation of the Nrf2 in the CP/CPPS rat model.Discussion and Conclusions: The findings in this study suggest that lycopene exerts potent anti‐ CP/CPPS Seffects through alleviating inflammatory response and oxidative stress, which is probably attributed to the interaction of NF‐κB, MAPKs, and Nrf2 signaling pathways in rats. As a natural antioxidant, lycopene may serve as a promising pharmaceutical preparation for treating CP/CPPS.