Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells

Levina, Elina; Jiang, Hao; Chen, Mengqiang; Baig, Mirza S.; Oliver, David J.; Ohouo, Patrice; Lim, Chang-Uk; Schools, Garry; Carmack, S.; Ding, Ye; Broude, Eugenia V.; Roninson, Igor B.; Buttyan, Ralph; Shtutman, Michael

doi:10.18632/oncotarget.3743

Cited by 20 publications

(19 citation statements)

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“…This hyperactivity may result from AR gene amplification, increased rate of AR gene transcription and/or increased AR transcript stability [13, 14], expression of constitutively active ligand-independent AR splice variants, or AR mutations that facilitate activation by non-androgens [15]. Moreover, the previously mentioned intratumoral steroidogenesis and overexpression of AR co-activators in tumor cells may also contribute to the hyperactivity of AR in CRPC [15]. In some PCa cell lines, androgen independence and elevated AR signaling can be attributed to AR trans-repressors and trans-activators.…”

Section: Role Of Androgens and Ar In Pca Progressionmentioning

confidence: 99%

“…A recent publication identified 20 human genes that regulate expression of AR responsive genes in the absence of androgens. Among them, IGSF8 and RTN1 are shown to negatively regulate the progression from androgen dependence (castration sensitive) to an androgen-independent (castration resistant) state; their down-regulation enabled castration resistant cell proliferation of androgen-dependent PCa cells [15]. While strategies that inhibit androgen synthesis or interfere with androgen-AR interaction ultimately fail in the treatment of CRPC, methods which target the synthesis or activity of AR remain powerful therapeutic options [2].…”

Section: Role Of Androgens and Ar In Pca Progressionmentioning

confidence: 99%

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Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

Kallifatidis

Hoy

Lokeshwar

2016

Seminars in Cancer Biology

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Prostate cancer (PCa), a hormonally-driven cancer, ranks first in incidence and second in cancer related mortality in men in most Western industrialized countries. Androgen and androgen receptor (AR) are the dominant modulators of PCa growth. Over the last two decades multiple advancements in screening, treatment, surveillance and palliative care of PCa have significantly increased quality of life and survival following diagnosis. However, over 20% of patients initially diagnosed with PCa still develop an aggressive and treatment-refractory disease. Prevention or treatment for hormone-refractory PCa using bioactive compounds from marine sponges, mushrooms, and edible plants either as single agents or as adjuvants to existing therapy, has not been clinically successful. Major advancements have been made in the identification, testing and modification of the existing molecular structures of natural products. Additionally, conjugation of these compounds to novel matrices has enhanced their bio-availability; a big step towards bringing natural products to clinical trials. Natural products derived from edible plants (nutraceuticals), and common folk-medicines might offer advantages over synthetic compounds due to their broader range of targets, as compared to mostly single target synthetic anticancer compounds; e.g. kinase inhibitors. The use of synthetic inhibitors or antibodies that target a single aberrant molecule in cancer cells might be in part responsible for emergence of treatment refractory cancers. Nutraceuticals that target AR signaling (epigallocatechin gallate [EGCG], curcumin, and 5α-reductase inhibitors), AR synthesis (ericifolin, capsaicin and others) or AR degradation (betulinic acid, di-indolyl diamine, sulphoraphane, silibinin and others) are prime candidates for use as adjuvant or mono-therapies. Nutraceuticals target multiple pathophysiological mechanisms involved during cancer development and progression and thus have potential to simultaneously inhibit both prostate cancer growth and metastatic progression (e.g., inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and proliferation). Given their multi-targeting properties along with relatively lower systemic toxicity, these compounds offer significant therapeutic advantages for prevention and treatment of PCa. This review emphasizes the potential application of some of the well-researched natural compounds that target AR for prevention and therapy of PCa.

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Section: Role Of Androgens and Ar In Pca Progressionmentioning

confidence: 99%

Section: Role Of Androgens and Ar In Pca Progressionmentioning

confidence: 99%

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

Kallifatidis

Hoy

Lokeshwar

2016

Seminars in Cancer Biology

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“…RTN1-C overexpression sensitizes cancer cells to chemotherapeutic-induced apoptosis through p53-independent pathways (Di Sano et al 2003). In androgen-dependent LNCaP prostate cancer cells, knock down using siRNA targeting all RTN1 transcript isoforms enabled androgen independent growth of these cells (Levina 2015). Gastrointestinal stromal tumors (GISTs) with mutations in KIT or PDGFRA show frequent alterations of the 14q23.1 region, which includes the RTN1 gene (Astolfi et al 2010).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Lemire

Loo

et al. 2015

Hum Genet

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Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of CR polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC (p=2.5×10−10; odds ratio estimated by re-including all controls (OR)=0.87, 95% confidence interval (CI): 0.83–0.91; minor allele frequency (MAF)=13%). Results were replicated in samples of African descent (1,894 cases and 4,703 controls; p=0.01; OR=0.86, 95% CI: 0.77–0.97; MAF=16%). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p=0.001), a protein-coding gene involved in survival and proliferation of cancer cells that is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p=1.3×10−8).

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“…The genes TMEM176A and TMEM176B are likely candidates for association with navel length traits, are orthologous in humans and constitute the Androgen Induced 1 cluster (AIG1, Id: GO:0005525). Genes belonging to this cluster have been related with prostate cancer because of their important role in regulating apoptosis and maintaining the cell cycle (Levina et al, 2015). The absence of any detected relationship between the genes identified for coat-and SC traits with the gene clusters is probably because these genes act independently.…”

Section: Traitsmentioning

confidence: 99%

Prospecting genes associated with navel length, coat and scrotal circumference traits in Canchim cattle

Romero

Siqueira²,

Santiago

et al. 2018

Livestock Science

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A B S T R A C TThe aim of this work was to identify genomic regions and genes in association with the navel length, coat and scrotal circumference traits of Canchim breed of cattle, using genome-wide association studies (GWAS). Imputed data from single nucleotide polymorphism type markers were used, with accuracy greater than 95%. The analyses of genome-wide association were conducted by the Bayes B method, implemented in the GenSel program. Non-overlapping windows that explained at least 0.19% of the additive genetic variance were considered as significant, this value corresponds five times the expected for 1 Mb size windows. GWAS indicated 31 regions in association with navel length, one coat region, and four SC-related regions. In these regions, 4 quantitative loci (QTLs) related to navel length and 5 with SC were identified, as for the coat, the QTLs detected did not present previously described relation with this trait. Among the candidate genes in the associated regions, 7 genes were cited in previous studies, with biological functions related to navel length, one for coat and three for SC. The candidate genes TMEM176A and TMEM176AB, which are orthologous in humans, are in association with navel's trait and compose the Androgen Induced 1 cluster. The identification of genes and QTLs, with a function related to the studied traits, previously described in the literature, reinforces the evidence that the found regions are associated with navel length, coat and SC. This information may contribute to the understanding of the genetic architecture involved with of these traits, to guiding genetic validation studies, gene introgression and contribute to include information concerning molecular markers in genetic evaluation of animal improvement programs.

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Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells

Cited by 20 publications

References 96 publications

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1

Prospecting genes associated with navel length, coat and scrotal circumference traits in Canchim cattle

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