Regression Of Prostate Cancer Research Articles

Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model.

Objective: Obesity resulting from high-fat diets has a close relationship with the morbidity and mortality associated with Prostate cancer (PCa) in males. The anti-cancer role of Icaritin (ICT, a traditional Chinese herbal medicine) has been reported in several types of cancer including PCa. Adipokines are novel adipocyte-specific secretory protein, which plays a key role in the development of various diseases including obesity, diabetes, atherosclerosis, and cancer. However, the function of ICT and the molecular mechanisms underlying its role in PCa regression through modulation of adipokines have not been studied. Here, we assessed the anti-cancer properties of ICT under the influence of human epidermal growth factor receptor type 2 (HER2) pathway modulating adipokines in obese PCa models.Materials and Methods: In this study, we used transgenic adenocarcinoma of mouse prostate (TRAMP), a well-established animal model for the study of PCa pathogenesis. All the animals were fed on a high-fat diet (HFD with 40% fat) and divided into two groups, one received ICT solution of 30 mg/kg body bwt (i.p) while the other group served as control without any ICT treatment. The mortality rate, tumor formation and fat ratio were assessed by histopathological and magnetic resonance analysis at different time points of 20th, 24th and 28th weeks. The protein expression of HER2 and serum levels of adipokines were measured using western blotting, IHC and multiplex immunoassays. The PCa grade in 12 TRAMP mice were longitudinally evaluated to visualize PCa development and progression upon post-surgery using PET/CT scanning.Results: We observed that ICT treatment significantly reduces the total mortality rate of TRAMP mice (p = 0.045) and the percentage of prostate intraepithelial neoplasia (PIN) or PCa (p = 0.029). Interestingly, significantly decreased levels of leptin (p = 0.006 @20th wk) and the elevated levels of adiponectin (p = 0.030 @20th wk) were observed in different subgroups upon ICT treatment in a time-dependent manner. In addition, a decrease level of HER2 (p = 0.032 @28th wk) and an elevated level of PEA3 (p = 0.014 @28th wk) were also detected in ICT treated group. The PET/CT-based imaging showed that ICT vs non-ICT treated mice had different standard uptake value and metastasis.Discussion and Conclusion: Our results showed potent anti-cancer properties of ICT through the modulation of adipokine secretion may alter the expression and activation of HER2 pathway as an alternative mechanism to prevent PCa progression. Altogether, our findings indicate that ICT could be a promising cancer preventive agent with the potential to target and eradicate tumor cells in obese PCa patients.

Anticancer effect of icaritin on prostate cancer via regulating miR-381-3p and its target gene UBE2C.

Prostate cancer (PCa) is one of the most common health‐related issues in the male individuals of western countries. Icaritin (ICT) is a traditional Chinese herbal medicine that exhibits antitumor efficacy in variety of cancers including PCa. However, the precise function and detailed molecular mechanism of ICT in the regression of PCa remain unclear. Ubiquitin‐conjugating enzyme E2C (UBE2C) is an anaphase‐promoting complex/cyclosome (APC/C)‐specific ubiquitin conjugating enzyme, which acts as an oncogene in PCa progression. The function of ICT in PCa was investigated in transgenic adenocarcinoma mouse prostate (TRAMP) mice using survival analysis, hematoxylin and eosin (HE) staining, TUNEL assay, and immunohistochemistry and in human PCa cell lines using various molecular techniques and functional assays including plasmid construction and transfection. Bioinformatic analyses were performed to identify the interaction between miRNA and UBE2C via the TargetScan algorithm. We demonstrated that ICT inhibited the development and progression of PCa in TRAMP mice by improving the survival rate and tumor differentiation. Furthermore, we found that ICT could significantly inhibit cell proliferation and invasion and induce apoptosis in PCa cells. Consistently, downregulation of UBE2C suppressed the proliferation and invasion of PCa cells. Moreover, a luciferase reporter assay confirmed that UBE2C was a direct target of miR‐381‐3p. Meanwhile, ICT simultaneously downregulated UBE2C expression and upregulated miR‐381‐3p levels in human PCa cells. Altogether, our findings provide a strong rationale for the clinical application of ICT as a potential oncotherapeutic agent against PCa via a novel molecular mechanism of regulating the miR‐381‐3p/UBE2C pathway.

Abstract 5456: The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer.

Abstract The androgen receptor (AR) plays a central role in the development of castration-resistant prostate cancer (CRPC), which is a major challenge for hormone therapy of advanced/metastatic prostate cancer (PCa). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination-dependent degradation, and this promotes the subsequent recruitment of p300-bound, transcriptionally active AR to a select group of AR target gene promoters/enhancers. Consequently, Siah2 promotes the expression of ∼13% of androgen-responsive genes involved in lipid metabolism, cell motility and proliferation. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under the androgen-deprivation condition in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity. Citation Format: Jianfei Qi, Manisha Tripathi, Natasha Sahgal, Ladan Fazil, Susan Ettinger, William J. Placzek, Giuseppina Claps, Leland W.K. Chung, David Bowtell, Martin Gleave, Neil Bhowmick, Ze'ev Ronai. The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5456. doi:10.1158/1538-7445.AM2013-5456 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

QUANTITATIVE BONE SCINTIGRAPHY. A methodological evaluation in prostate cancer

Purpose: To evaluate a simple method for quantification of focal activity in bone scintigraphy (BS). Material and Methods: The gamma camera was calibrated using a phantom. Quantitative bone scintigraphy (QBS) was performed on 11 men recently diagnosed with prostate cancer (PCa), for whom routine BS showed involvement of the skeleton. Following endocrine therapy for 4 to 8 months, a second QBS was performed. Changes in QBS values were then compared to changes in serum levels of prostate-specific antigen (PSA). Results: PSA response indicating regression of PCa was accompanied by a decrease in the QBS value in 8 of the 11 patients. The overall mean error of the QBS values was 15%. Conclusion: QBS according to this method is a relatively simple procedure that might contribute to objective evaluation of therapeutic effects in skeletal metastases, although its validity must be tested in a larger clinical material.

Quantitative bone scintigraphy: A methodological evaluation in prostate cancer

To evaluate a simple method for quantification of focal activity in bone scintigraphy (BS). The gamma camera was calibrated using a phantom. Quantitative bone scintigraphy (QBS) was performed on 11 men recently diagnosed with prostate cancer (PCa), for whom routine BS showed involvement of the skeleton. Following endocrine therapy for 4 to 8 months, a second QBS was performed. Changes in QBS values were then compared to changes in serum levels of prostate-specific antigen (PSA). PSA response indicating regression of PCa was accompanied by a decrease in the QBS value in 8 of the 11 patients. The overall mean error of the QBS values was 15%. QBS according to this method is a relatively simple procedure that might contribute to objective evaluation of therapeutic effects in skeletal metastases, although its validity must be tested in a larger clinical material.