scholarly journals A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 14
Author(s):  
Marzia Di Donato ◽  
Pia Giovannelli ◽  
Maria Vittoria Barone ◽  
Ferdinando Auricchio ◽  
Gabriella Castoria ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
3D Models ◽  
Biologically Active ◽  
New Drugs ◽  
Filamin A ◽  
Complex Assembly ◽  
Prostate Cancer Development ◽  
Hormone Antagonists ◽  
Peptide Targeting

Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone antagonists.

scholarly journals The androgen receptor/filamin A complex as a target in prostate cancer microenvironment

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marzia Di Donato ◽  
Alice Zamagni ◽  
Giovanni Galasso ◽  
Erika Di Zazzo ◽  
Pia Giovannelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Associated Fibroblasts ◽  
Filamin A ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells ◽  
Complex Assembly ◽  
Efficient Treatment

AbstractProstate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signaling pathways. Tumor microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumor area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. This study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer.

scholarly journals Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer

2015 ◽  
Vol 22 (3) ◽  
pp. 369-386 ◽  
Author(s):  
Rosalinda M Savoy ◽  
Liqun Chen ◽  
Salma Siddiqui ◽  
Frank U Melgoza ◽  
Blythe Durbin-Johnson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Ubiquitin Ligase ◽  
Scaffolding Protein ◽  
Filamin A ◽  
Androgen Response Element ◽  
Castration Resistant ◽  
Suppression Mechanism ◽  
Transcription Expression ◽  
Transcription Program

Prostate cancer (PCa) progression is regulated by the androgen receptor (AR); however, patients undergoing androgen-deprivation therapy (ADT) for disseminated PCa eventually develop castration-resistant PCa (CRPC). Results of previous studies indicated thatAR, a transcription factor, occupies distinct genomic loci in CRPC compared with hormone-naïve PCa; however, the cause of this distinction was unknown. The E3 ubiquitin ligaseNrdp1is a model AR target modulated by androgens in hormone-naïve PCa but not in CRPC. UsingNrdp1, we investigated how AR switches transcription programs during CRPC progression. The proximalNrdp1promoter contains an androgen response element (ARE); we demonstrated AR binding to this ARE in androgen-sensitive PCa. Analysis of hormone-naive human prostatectomy specimens revealed correlation betweenNrdp1and AR expression, supporting AR regulation of NRDP1 levels in androgen-sensitive tissue. However, despite sustained AR levels, AR binding to theNrdp1promoter andNrdp1expression were suppressed in CRPC. Elucidation of the suppression mechanism demonstrated correlation of NRDP1 levels with nuclear localization of the scaffolding protein filamin A (FLNA) which, as we previously showed, is itself repressed following ADT in many CRPC tumors. Restoration of nuclear FLNA in CRPC stimulated AR binding toNrdp1ARE, increased its transcription, and augmented NRDP1 protein expression and responsiveness to ADT, indicating that nuclear FLNA controls AR-mediated androgen-sensitiveNrdp1transcription. Expression of other AR-regulated genes lost in CRPC was also re-established by nuclear FLNA. Thus, our results indicate that nuclear FLNA promotes androgen-dependent AR-regulated transcription in PCa, while loss of nuclear FLNA in CRPC alters the AR-regulated transcription program.

scholarly journals The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

2019 ◽  
Vol 11 (503) ◽  
pp. eaaw4993 ◽  
Author(s):  
Yuzhen Liu ◽  
Jessie L. Horn ◽  
Kalyan Banda ◽  
Asha Z. Goodman ◽  
Yiting Lim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Translation Initiation ◽  
Transcriptional Control ◽  
Regulatory Element ◽  
Negative Regulator ◽  
Mrna Transcription ◽  
Posttranscriptional Gene Regulation ◽  
Prostate Cancer Development

The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.

Co-assessment of cytoplasmic and nuclear androgen receptor location in prostate specimens: potential implications for prostate cancer development and prognosis

2008 ◽  
Vol 101 (10) ◽  
pp. 1302-1309 ◽  
Author(s):  
Jean-Simon Diallo ◽  
Abdulhadi Aldejmah ◽  
Abdelali Filali Mouhim ◽  
Mona Alam Fahmy ◽  
Ismaël Hervé Koumakpayi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Development ◽  
Prostate Cancer Development

scholarly journals Germ-Line Genetic Variation in the Key Androgen-Regulating Genes Androgen Receptor, Cytochrome P450, and Steroid-5-α-Reductase Type 2 Is Important for Prostate Cancer Development

2006 ◽  
Vol 66 (22) ◽  
pp. 11077-11083 ◽  
Author(s):  
Sara Lindström ◽  
Fredrik Wiklund ◽  
Hans-Olov Adami ◽  
Katarina Augustsson Bälter ◽  
Jan Adolfsson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Variation ◽  
Cytochrome P450 ◽  
Androgen Receptor ◽  
Germ Line ◽  
Cancer Development ◽  
Prostate Cancer Development

scholarly journals Synthesis of novel andostane-N-cyclohexyl-17-carboxamides, and their effect on the 5α-reductase isoform 2, the androgen receptor, and androgen-dependent glands

2021 ◽  
Author(s):  
Juan Carlos Lopez-Lezama ◽  
Marisa Cabeza ◽  
Yvonne Heuze ◽  
Araceli Sánchez ◽  
José L. Rojas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Biological Activity ◽  
Androgen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
Seminal Vesicles ◽  
Prostatic Hyperplasia ◽  
New Drugs ◽  
Binding Assays ◽  
Competitive Binding Assays

Background: Benign Prostatic Hyperplasia (BPH), and Prostate Cancer (PCa) are androgen-dependent diseases. PCa is associated with excessive signalling of the androgen receptor (AR) due to the binding of 5α-DHT and T. BPH is related to high levels of 5α-dihydrotestosterone (5α-DHT), biosynthesized from testosterone (T) by 5α-reductase (5RD5A). The inhibition of 5RD5A and the blockage of AR are targets for their treatment. In this study, the synthesis and determination of biological activity of the new N-cyclohexyl-3β-hydroxyandrosta-5,16-diene-17-carboxamide (6), N-cyclohexyl-3-oxoandrosta-4,6,16-triene-17-carboxamide (7), and N-cyclohexyl-3-oxoandrosta-4,16-diene-17-carboxamide (8) were carried out to find new drugs to improve these afflictions. Methods: The synthesis of 6 to 8 was confirmed by spectroscopic and spectrometric analyses. Competitive binding assays determined the affinity of 6 to 8 to the AR. The inhibitory activity of 5RD5A isoform 2 (5RD5A2) (IC50) was established by the conversion of [3H]-T to [3H]-5α-DHT and it was compared with finasteride (FIN). The pharmacological effect of 6 to 8 was determined on the weight of the prostate and seminal vesicles glands of castrated hamsters treated with T, and on the diameter size of their flank organs. Results: Compounds 7 and 8 bound lightly (ca. 15 %) to AR. Comparing to FIN (IC50 = 8.5 nM), 6 to 8 (IC50 = 0.169, 0.105 and 0.155 nM, respectively) showed higher potency as inhibitors of 5RD5A2. Compound 6 decreased the prostate and seminal vesicles weight, as well as the hamsters' diameter flank organs. However, 7 only decreased the diameter of flank organs. Surprisingly, 8 increased these pharmacological parameters. Conclusion: Androstane-17-caboxamide 6 is a 5RD5A2 inhibitor that reduces the weight of androgen-dependent glands such as the prostate, suggesting it could be a lead for new drugs to treat BPH and PCa.

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