Stromal–epithelial interaction is crucial to mediate normal prostate and prostate cancer (PCa) development. The indispensable roles of mesenchymal/stromal androgen receptor (AR) for the prostate ...organogenesis have been demonstrated by using tissue recombination from wild‐type and testicular feminized mice. However, the stromal AR functions in the tumour microenvironment and the underlying mechanisms governing the interactions between the epithelium and stroma are not completely understood. Here, we have established the first animal model with AR deletion in stromal fibromuscular cells (dARKO, AR knockout in fibroblasts and smooth muscle cells) in the Pten+/− mouse model that can spontaneously develop prostatic intraepithelial neoplasia (PIN). We found that loss of stromal fibromuscular AR led to suppression of PIN lesion development with alleviation of epithelium proliferation and tumour‐promoting microenvironments, including extracellular matrix (ECM) remodelling, immune cell infiltration and neovasculature formation due, in part, to the modulation of pro‐inflammatory cytokines/chemokines. Finally, targeting stromal fibromuscular AR with the AR degradation enhancer, ASC‐J9®, resulted in the reduction of PIN development/progression, which might provide a new approach to suppress PIN development.
Vasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple ...cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metastatic RCC, sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation. Previously we identified that the estrogen receptor β (ERβ) functions as an oncogenic factor to promote RCC progression, supported by the analytic results from The Cancer Genome Atlas (TCGA) database. We have also found evidence that sunitinib induces RCC VM formation by up-regulating ERβ expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ERβ expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ERβ expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ERβ transcriptionally up-regulates the circular RNA of DGKD (circDGKD, hsa_circ_0058763), which enhances VE-cadherin expression by sponging the microRNA miR-125-5p family. Targeting circDGKD intercepts sunitinib-pretreatment-induced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ERβ/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC.
Early studies demonstrated that whole‐body androgen receptor (AR)–knockout mice with hypogonadism exhibit insulin resistance. However, details about the mechanisms underlying how androgen/AR ...signaling regulates insulin sensitivity in individual organs remain unclear. We therefore generated hepatic AR‐knockout (H‐AR−/y) mice and found that male H‐AR−/y mice, but not female H‐AR−/− mice, fed a high‐fat diet developed hepatic steatosis and insulin resistance, and aging male H‐AR−/y mice fed chow exhibited moderate hepatic steatosis. We hypothesized that increased hepatic steatosis in obese male H‐AR−/y mice resulted from decreased fatty acid β‐oxidation, increased de novo lipid synthesis arising from decreased PPARα, increased sterol regulatory element binding protein 1c, and associated changes in target gene expression. Reduced insulin sensitivity in fat‐fed H‐AR−/y mice was associated with decreased phosphoinositide‐3 kinase activity and increased phosphenolpyruvate carboxykinase expression and correlated with increased protein‐tyrosine phosphatase 1B expression. Conclusion: Together, our results suggest that hepatic AR may play a vital role in preventing the development of insulin resistance and hepatic steatosis. AR agonists that specifically target hepatic AR might be developed to provide a better strategy for treatment of metabolic syndrome in men. (HEPATOLOGY 2008.)
The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT ...eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
RRR-alpha-tocopheryl succinate (alpha-vitamin E succinate, VES), one of the vitamin E derivatives, can effectively inhibit the proliferation of human prostate cancer cells. However, little is known ...about its effect on prostate cancer cell invasive ability. Tumor metastasis is a complex process and the extracellular matrix (ECM) is the first barrier that tumor cells encounter. Therefore, we tested the effect of VES on the invasion of different prostate tumor cells, PC-3, DU-145, and LNCaP, through Matrigel, a reconstituted ECM, using an in vitro cell invasion assay. The invasion of PC-3 and DU-145 cells through Matrigel was inhibited by 20 microM VES after treating for 24 h. The condition did not alter cell survival, cell cycle, cell adhesion or cell motility. We further investigated whether the ability of VES to inhibit prostate cancer cell invasiveness was associated with its ability to inhibit the activity of matrix metalloproteinases (MMPs), the key enzymes in the proteolysis of basement membrane during invasion. PC-3 and DU-145 cells that were treated with VES showed a significant reduction in the levels of MMP-9 in the culture medium. In contrast, LNCaP cells, which did not secrete MMP-9, were poorly invasive in Matrigel and were hardly affected by treatment with VES. This is the first report suggesting that VES inhibits human prostate cancer cell invasiveness and the reduction of secreted MMP-9 activity could be one of the contributory factors, which points to the potential use of VES in the prevention and therapy of prostate cancer invasion.
Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the ...stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9(®), led to the reduction of prostate size, which could be used in future therapy.
In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor ...(AR⁻/⁻) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR⁻/⁻ mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR⁺/⁺) oocytes had reached metaphase II. Interestingly, we found these AR⁻/⁻ female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells.
Whereas several apoptosis-related proteins have been linked to the antiapoptotic effects of Akt serine-threonine kinase, the search continues to explain the Akt signaling role in promoting cell ...survival via antiapoptotic effects. Here, we demonstrate that Akt phosphorylates the androgen receptor (AR) at Ser-210 and Ser-790. A mutation at AR Ser-210 results in the reversal of Akt-mediated suppression of AR transactivation. Activation of the phosphatidylinositol-3-OH kinase/Akt pathway results in the suppression of AR target genes, such as p21, and the decrease of androgen/AR-mediated apoptosis, which may involve the inhibition of interaction between AR and AR coregulators. Together, these findings provide a molecular basis for cross-talk between two signaling pathways at the level of Akt and AR-AR coregulators that may help us to better understand the roles of Akt in the androgen/AR-mediated apoptosis.
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