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BACKGROUND: The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL), used in bipolar androgen therapy, inhibits growth of PCa suggesting a tumor-suppressive activity by SAL. SAL was shown to induce cellular senescence in PCa. METHODS: RNA-seq and transcriptome analysis, ChIP-seq, human 3D PCa spheroids, mouse xenografted castration-resistant PCa, knockdown and overexpression, Co-immunoprecipitation (Co-IP), translocation analysis, immune detection, qRT-PCR, protein-protein interaction modelling. RESULTS: Here, mice xenografts with castration-resistant PCa tumors show that SAL inhibits cancer growth in vivo suggesting that SAL activates a tumor-suppressive mechanism. RNA-seq and ChIP-seq revealed the clock gene BHLHE40 is a novel direct AR target. Compared to adjacent human prostate tissues, the expression of BHLHE40 is reduced in PCa tumors and associated with reduced survival. Knockdown suggests that BHLHE40 mediates SAL-induced cellular senescence including tumor spheroids. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 and SAL leading to the identification of four classes of SAL-BHLHE40 transcriptome landscapes. Co-IP and modelling suggest binding of BHLHE40 to AR and their co-translocation into nucleus by SAL treatment. Further, RNA-seq and ChIP-seq analysis indicate that the atypical tumor suppressive cyclin G2 emerged as a novel downstream target of BHLHE40 and a mediator of SAL-induced cellular senescence. CONCLUSIONS: The data provide evidence of the tumor suppressive activity of SAL and a novel signaling by the AR-BHLHE40-CCNG2 axis for androgen-induced cellular senescence, linking circadian rhythm factor to androgen signaling as a novel tumor suppressive pathway.

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BACKGROUND: Prostate cancer (PCa) is a prevalent malignancy in men worldwide, ranking as the second leading cause of cancer-related death in Western countries. Various PCa hormone therapies, such as androgen receptor (AR)-antagonists or supraphysiological androgen level (SAL) reduce cancer cell proliferation. However, treated cells may influence the growth of neighboring cells through secreted exosomes in the tumor microenvironment (TME). Here, the change of protein content of exosomes secreted from PCa cells through treatment with different AR-antagonists or SAL has been analyzed. METHODS: Isolation of exosomes via ultracentrifugation of treated human PCa LNCaP cells with AR-agonist and various AR-antagonists; analysis of cellular senescence by detection of senescence associated beta galactosidase activity (SA ß-Gal); Western blotting and immunofluorescence staining; Mass spectrometry (MS-spec) of exosomes and bioinformatic analyses to identify ligand-specific exosomal proteins. Growth assays to analyze influence of exosomes on non-treated cells. RESULTS: MS-spec analysis identified ligand-specific proteins in exosomes. One thousand seventy proteins were up- and 52 proteins downregulated by SAL whereas enzalutamide upregulated 151 proteins and downregulated 42 exosomal proteins. The bioinformatic prediction indicates an up-regulation of pro-proliferative pathways. AR ligands augment hub factors in exosomes that include AKT1, CALM1, PAK2 and CTNND1. Accordingly, functional assays confirmed that the isolated exosomes from AR-ligand treated cells promote growth of untreated PCa cells. CONCLUSION: The data suggest that the cargo of exosomes is controlled by AR-agonist and -antagonists and distinct among the AR-antagonists. Further, exosomes promote growth that might influence the TME. This finding sheds light into the complex interplay between AR signaling and exosome-mediated communication between PCa cells.

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BACKGROUND: Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cancer cell resistance and many bypassing mechanisms to escape therapy. According to the intricacy of PCa, many standard therapies are being used depending on PCa stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation therapy, supraphysiological androgen, and AR antagonists) and chemotherapy. Most of the aforementioned therapies have been implicated to induce cellular senescence. Cellular senescence is defined as a stable cell cycle arrest in the G1 phase and is one of the mechanisms that prevent cancer proliferation. RESULTS: In this review, we provide and analyze different mechanisms of therapy-induced senescence (TIS) in PCa and their effects on the tumor. Interestingly, it seems that different molecular pathways are used by cancer cells for TIS. Understanding the complexity and underlying mechanisms of cellular senescence is very critical due to its role in tumorigenesis. The most prevalent analyzed pathways in PCa as TIS are the p53/p21WAF1/CIP1, the p15INK4B/p16INK4A/pRb/E2F/Cyclin D, the ROS/ERK, p27Kip1/CDK/pRb, and the p27Kip1/Skp2/C/EBP ß signaling. Despite growth inhibition, senescent cells are highly metabolically active. In addition, their secretome, which is termed senescence-associated secretory phenotype (SASP), affects within the tumor microenvironment neighboring non-tumor and tumor cells and thereby may regulate the growth of tumors. Induction of cancer cell senescence is therefore a double-edged sword that can lead to reduced or enhanced tumor growth. CONCLUSION: Thus, dependent on the type of senescence inducer and the specific senescence-induced cellular pathway, it is useful to develop pathway-specific senolytic compounds to specifically targeting senescent cells in order to evict senescent cells and thereby to reduce SASP side effects.

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Naturally, in somatic cells chromosome ends (telomeres) shorten during each cell division. This process ensures to limit proliferation of somatic cells to avoid malignant proliferation; however, it leads to proliferative senescence. Telomerase contains the reverse transcriptase TERT, which together with the TERC component, is responsible for protection of genome integrity by preventing shortening of telomeres through adding repetitive sequences. In addition, telomerase has non-telomeric function and supports growth factor independent growth. Unlike somatic cells, telomerase is detectable in stem cells, germ line cells, and cancer cells to support self-renewal and expansion. Elevated telomerase activity is reported in almost all of human cancers. Increased expression of hTERT gene or its reactivation is required for limitless cellular proliferation in immortal malignant cells. In hormonally regulated tissues as well as in prostate, breast and endometrial cancers, telomerase activity and hTERT expression are under control of steroid sex hormones and growth factors. Also, a number of hormones and growth factors are known to play a role in the carcinogenesis via regulation of hTERT levels or telomerase activity. Understanding the role of hormones in interaction with telomerase may help finding therapeutical targets for anticancer strategies. In this review, we outline the roles and functions of several steroid hormones and growth factors in telomerase regulation, particularly in hormone regulated cancers such as prostate, breast and endometrial cancer.

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PURPOSE: Prostate cancer (PCa) and benign prostate hyperplasia (BPH) are two prevalent disorders among men with considerable mortality and morbidity. Several association studies have been conducted in different populations to find genetic loci linked with these disorders. Retinoic acid-receptor-related orphan receptor alpha (RORA) codes for a transcription factor which regulates expression of several cancer-related genes. Besides, RORA has been shown to be down-regulated in PCa tissues and cell lines. MATERIALS AND METHODS: In the present study we evaluated genotype and allele frequencies of rs11639084 and rs4774388 variants within RORA gene in PCa and BPH patients compared with healthy subjects. RESULTS: The rs11639084 and rs4774388 alleles were not different between PCa and normal groups 95% CI: 0.52-1.24, OR = 1.04, P = .34; 95% CI: 0.48-1.33, OR = .79, P = .39 respectively. Moreover, we did not detect any significant difference in allele, genotype or haplotype frequencies of these SNPs between the other study groups. CONCLUSION: The mentioned RORA variants are possibly not involved in the pathogenesis of PCa and BPH. Future studies are needed to assess the associations between other variant within this gene and PCa risk to suggest a putative mechanism for involvement of RORA in PCa.

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PURPOSE: Tumor necrosis factor-α has been suggested to play a crucial role in the development andprogression of hepatocellular carcinoma (HCC). Previous reports have indicated that rs361525 and rs1800629 might be risk factors for various cancers. Increasing studies have been conducted on the association of these two SNPs with HCC risk but the results remain inconclusive. METHODS: In order to detect association between TNF- α and HCC, a meta-analysis was performed. Five studies with 541 cases and 795 controls were used for rs361525, while six studies including 925 cases and 1307 controls were collected for investigating rs1800629. The grouping of countries from data were obtained was done by Principal Coordinate Analysis plot (PCA). Moreover, association between geographical area and grouping of genotypes was determined by Canonical Correspondence Analysis (CCA). RESULTS: Our meta-analysis showed that rs361525 and rs1800629 were not significantly associated with the risk of HCC. CCA analysis illustrated that there was not any correlation between genotype distribution and geographical distance for rs1800629 but there was significant correlation between genotype distribution and geographical features for rs361525. PCA analysis for both SNPs showed India and Korea were placed near each other and also China and Brazil were in same part of PCA plot. CONCLUSION: To sum up, this meta-analysis suggests that the rs361525 and rs1800629 are not associated with HCC development while geographical distance effect on rs361525 genetic inheritance but not effect on rs1800629. However, it is necessary to conduct further studies with larger sample. Moreover, gene-gene and gene-environment interactions should also be considered.

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