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INTRODUCTION AND OBJECTIVE:AR/AR-V7 and AKR1C3 play key roles in prostate cancer progression and drive resistance to current therapies. Thus far, there are no clinically available therapies to spec...

INTRODUCTION AND OBJECTIVE:Inhibition of poly (ADP-ribose) polymerase (PARP) is an exciting treatment strategy recently approved for prostate cancer patients with homologous recombination repair de...

INTRODUCTION AND OBJECTIVE:Protein homeostasis is altered during prostate cancer progression mediated by a comphrehensive network including the ubiquitin-proteasome-system. This effect is primarily...

INTRODUCTION AND OBJECTIVE:Steroid sulfatase (STS) is a key enzyme that catalyzes the hydrolysis of DHEAS to the biologically active DHEA, which is further metabolized to active androgens that bind...

INTRODUCTION AND OBJECTIVES:The resistant mechanisms of next generation anti-androgens in castration resistant prostate cancer are incompletely understood. Our previous work demonstrated that AKR1C...

INTRODUCTION AND OBJECTIVES:Proteostasis is a complementary process by which cells control the protein biosynthesis, folding, trafficking and degradation. Evidence suggests that proteomic instability, such as protein misfolding and aggregation plays pivotal roles in cancer cell survival and progression. AR-V7 lacking the ligand binding domain confers resistance to enzalutamide and abiraterone in prostate cancer, targeting AR-V7 is an logical strategy to overcome the resistance. However, the mechanisms of AR-V7 proteostasis have not been fully studied so far. The objectives of this project are to investigate the roles of proteostasis in regulating AR-V7 expression and sensitivity to enzalutamide and abiraterone treatment.METHODS:Expression of HSP70 and STUB1 was determined by qRT-PCR and western blot. Expression of HSP70 and STUB1 was downregulated using specific siRNA. HSP70/STUB1 and AR-V7 interaction was determined by co-immunoprecipitation and dual immunofluorescence. The gene regulating mechanisms und...

highly expressed in metastatic and recurrent prostate cancer and in enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance. CONCLUSIONS: AKR1C3 activation and resulting in an increase in intracrine androgens are critical resistance mechanisms confer resistance to enzalutamide. Targeting AKR1C3 activation may provide a potential treatment strategy for metastatic prostate cancer patients who develop resistance to enzalutamide.

PURPOSE. Use of enzalutamide has improved the treatment of advanced prostate cancer. However, resistance to enzalutamide can develop frequently in initial responders. This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide. EXPERIMENTAL DESIGN. Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR, ELISA, and Western blotting were performed to detect expression levels of IL-6, c-Myc, survivin, and AR. Expression of Stat3 was downregulated using siRNA specific to Stat3. ChIP assay was performed to examine recruitment of AR to the PSA promoter. RESULTS. Prostate cancer cells expressing autocrine IL-6 are resistant to enzalutamide and autocrine IL-6 leads to constitutive activation of Stat3 and its target genes. Down regulation of Stat3 led to an increase in sensitivity of prostate cancer cells to enzalutamide. Overexpression of constitutively active Stat3 in prostate cancer cells induced resistance to enzalutamide treatment. Constitutively active Stat3 also enhanced the recruitment of AR to PSA promoter which could not be disrupted by enzalutamide. The Stat3 inhibitor AG490 reversed enzalutamide resistance in prostate cancer cells, while combination treatment with enzalutamide and AG490 significantly inhibited cell growth and induced cell apoptosis. CONCLUSIONS. This study demonstrates that the autocrine IL-6 pathway induces enzalutamide resistance in prostate cancer cells via the constitutive activation of Stat3. Co-targeting IL6-Stat3 pathway with enzalutamide may be utilized for treatment of advanced prostate cancer. Prostate 74:201–209, 2014. # 2013 Wiley Periodicals, Inc.

INTRODUCTION AND OBJECTIVES: Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor implicated in prostate carcinogenesis and progression. Stat3 activation is associated with prostate cancer development and progression. Constitutively activated Stat3 activates androgen receptor signaling and promotes castration-resistant prostate cancer growth. Targeting Stat3 activation is an effective strategy in prostate cancer therapy. METHODS: DU145, C4-2B and LNCaP cells were treated with sanguinarine for 4 hours and then stimulated with Interleukin-6 (IL-6) or vehicle. The phosphorylation status of STAT3 and related proteins were measured with western blots. Activation of transcription by STAT3 via the STAT3 responsive element was measured with luciferase reporter assay. The effect of sanguinarine on DU145 and LN/S17 cells anchorage-independent growth were examined with soft agar assay. The effect of sanguinarine on cells migration and invasion of DU145 cells were measured with scratch assay and invasion assay respectively. RESULTS: Exposure to micromolar concentrations of sanguinarine resulted in suppression of constitutive as well as IL6-induced phosphorylation of STAT3 at both Tyr705 and Ser727 in DU145 cells. The inhibition of STAT3 phosphorylation correlated with the inhibition of Janus-activated Kinase 2 (JAK2) and src phosphorylation. Sanguinarine inhibited the constitutive and IL6-induced STAT3 responsive element luciferase activities. Several STAT3 regulated genes such as c-myc and survivin were downregulated by sanguinarine. We found that sanguinarine inhibited the migration and invasion of DU145 cells that express constitutively activated STAT3. Furthermore, sanguinarine inhibited the anchorage-independent growth of DU145 and LN/S17 cells and suppressed the growth of DU145 xenografts in nude mice. CONCLUSIONS: These data suggest that sanguinarine targets multiple upstream kinases that mediate STAT3 activity. Sanguinarine is a potent STAT3 inhibitor that could be developed as a therapeutic agent for prostate cancer.

Olympus BX61WI upright frame and a modified Bio-Rad MRC 1024 scanhead was used. The corresponding tissues were subjected to hematoxylin and eosin staining for histologic confirmation of the structures. RESULTS: High-resolution images of the periprostatic tissue, nerves, prostate capsule, underlying acini, and individual acinar cells were obtained at varying magnifications (Figure). Histologic confirmation and correlation of the periprostatic tissue, prostate gland, fat, blood vessels, and nerves validated the findings of MPM. CONCLUSIONS: We have utilized a novel approach for tissue imaging which appears to provide microscopy level resolution in fresh tissue, without the need for any extrinsic labeling agents. This may allow for more accurate surgical decision making during nerve sparing radical prostatectomy and will also improve the accuracy of prostate biopsy when used to guide tissue sampling, once the technology is clinically translated.