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 Prostate Cancer Progression: Aspirin Causes Cell Cycle Quiescence in Prostate Cancer Cells

2018 ◽  
Vol 55 ◽  
pp. S11-S12 ◽  
Author(s):  
P. Oluseyi Olalekan Olaniyi ◽  
H. Whiteland ◽  
U.K. Shah ◽  
O. Bodger ◽  
J. Verma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells

scholarly journals Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer

2005 ◽  
Vol 12 (4) ◽  
pp. 805-822 ◽  
Author(s):  
Suresh Veeramani ◽  
Ta-Chun Yuan ◽  
Siu-Ju Chen ◽  
Fen-Fen Lin ◽  
Juliette E Petersen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Prostatic Acid Phosphatase ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells ◽  
Her 2 ◽  
Androgen Independent

Human prostatic acid phosphatase (PAcP) was used as a valuable surrogate marker for monitoring prostate cancer prior to the availability of prostate-specific antigen (PSA). Even though the level of PAcP is increased in the circulation of prostate cancer patients, its intracellular level and activity are greatly diminished in prostate cancer cells. Recent advances in understanding the function of the cellular form of PAcP (cPAcP) have shed some light on its role in prostate carcinogenesis, which may have potential applications for prostate cancer therapy. It is now evident that cPAcP functions as a neutral protein tyrosine phosphatase (PTP) in prostate cancer cells and dephosphorylates HER-2/ErbB-2/Neu (HER-2: human epidermal growth factor receptor-2) at the phosphotyrosine (p-Tyr) residues. Dephosphorylation of HER-2 at its p-Tyr residues results in the down-regulation of its specific activity, which leads to decreases in growth and tumorigenicity of those cancer cells. Conversely, decreased cPAcP expression correlates with hyperphosphorylation of HER-2 at tyrosine residues and activation of downstream extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling, which results in prostate cancer progression as well as androgen-independent growth of prostate cancer cells. These in vitro results on the effect of cPAcP on androgen-independent growth of prostate cancer cells corroborate the clinical findings that cPAcP level is greatly decreased in advanced prostate cancer and provide insights into one of the molecular mechanisms involved in prostate cancer progression. Results from experiments using xenograft animal models further indicate a novel role of cPAcP as a tumor suppressor. Future studies are warranted to clarify the use of cPAcP as a therapeutic agent in human prostate cancer patients.

scholarly journals REPS2/POB1 is downregulated during human prostate cancer progression and inhibits growth factor signalling in prostate cancer cells

Oncogene ◽  
2003 ◽  
Vol 22 (19) ◽  
pp. 2920-2925 ◽  
Author(s):  
Josien K Oosterhoff ◽  
Fred Penninkhof ◽  
Albert O Brinkmann ◽  
J Anton Grootegoed ◽  
Leen J Blok
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells ◽  
Growth Factor Signalling

scholarly journals A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells

Oncogene ◽  
2007 ◽  
Vol 26 (41) ◽  
pp. 6061-6070 ◽  
Author(s):  
Y Wang ◽  
J I Kreisberg ◽  
R G Bedolla ◽  
M Mikhailova ◽  
R W deVere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Filamin A ◽  
Prostate Cancer Cells

scholarly journals EZH2-TROAP Pathway Promotes Prostate Cancer Progression Via TWIST Signals

2021 ◽  
Vol 10 ◽  
Author(s):  
Lu Jin ◽  
Yibin Zhou ◽  
Guangqiang Chen ◽  
Guangcheng Dai ◽  
Kai Fu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells ◽  
Normal Tissues ◽  
Phase Cycle ◽  
Prostate Cancer Treatments

Trophinin-associated protein (TROAP) has been shown to be overexpressed and promotes tumor progression in some tumors. We performed this study to assess the biological and clinical significance of TROAP in prostate cancer. We downloaded TROAP mRNA expression data from TCGA and GEO databases. We analyzed expressions of TROAP and other genes in prostate cancer tumors at different stages and assessed Gleason scores. We used Celigo image, Transwell, and rescue assays, and flow cytometry detection to assess growth, apoptosis, proliferation, migration, and invasion of the prostate cancer cells. We identified and validated up- and down-stream genes in the TROAP pathway. The mRNA data suggested that TROAP expression was markedly upregulated in prostate cancer compared with its expression in normal tissues, especially in cancers with high stages and Gleason scores. Moreover, a high TROAP expression was associated with poor patient survival. Results of our in vitro assay showed that TROAP knockdown inhibited DU145 and PC3 cell proliferation and viability via cell apoptosis and S phase cycle arrest. The Transwell assay showed that TROAP knockdown inhibited cell migration and invasion, probably through MMP-9 and E-Cadherin modulation. Overexpression of TWIST partially abrogated the inhibitory effects of TROAP knockdown on prostate cancer cells. Our integrative mechanism dissection revealed that TROAP is in a pathway downstream of EZH2 and that it activates the TWIST/c-Myc pathway to regulate prostate cancer progression. In all, we identified TROAP as a driver of prostate cancer development and progression, providing a novel target for prostate cancer treatments.

scholarly journals Cerebral Cavernous Malformation 1 Determines YAP/TAZ Signaling-Dependent Metastatic Hallmarks of Prostate Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1125
Author(s):  
Sangryong Park ◽  
Ho-Yong Lee ◽  
Jayoung Kim ◽  
Hansol Park ◽  
Young Seok Ju ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cavernous Malformation ◽  
Cerebral Cavernous Malformation ◽  
Binding Motif ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells ◽  
Extraprostatic Extension ◽  
Upstream Regulators

Enhanced Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling is correlated with the extraprostatic extension of prostate cancer. However, the mechanism by which YAP/TAZ signaling becomes hyperactive and drives prostate cancer progression is currently unclear. In this study, we revealed that higher expression of CCM1, which is uniquely found in advanced prostate cancer, is inversely correlated with metastasis-free and overall survival in patients with prostate cancer. We also demonstrated that CCM1 induces the metastasis of multiple types of prostate cancer cells by regulating YAP/TAZ signaling. Mechanistically, CCM1, a gene mutated in cerebral cavernous malformation, suppresses DDX5, which regulates the suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. Our findings highlight the importance of CCM1-DDX5-YAP/TAZ signaling in the metastasis of prostate cancer cells.

scholarly journals Targeting Src-mediated Tyr216 phosphorylation and activation of GSK-3 in prostate cancer cells inhibit prostate cancer progression in vitro and in vivo

Oncotarget ◽  
2014 ◽  
Vol 5 (3) ◽  
pp. 775-787 ◽  
Author(s):  
Anna Goc ◽  
Belal Al-Husein ◽  
Katerina Katsanevas ◽  
Alison Steinbach ◽  
Uvette Lou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Cells

scholarly journals Androgen receptor in cancer-associated fibroblasts influences stemness in cancer cells

2017 ◽  
Vol 24 (4) ◽  
pp. 157-170 ◽  
Author(s):  
Chun-Peng Liao ◽  
Leng-Ying Chen ◽  
Andrea Luethy ◽  
Youngsoo Kim ◽  
Kian Kani ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Stem Cell Marker ◽  
Cancer Associated Fibroblasts ◽  
Cell Marker ◽  
Prostate Cancer Cells ◽  
Ifn Γ ◽  
Marker Expression

Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics. CAFs were isolated from the murine cPten−/−L prostate cancer model and cultured with human prostate cancer epithelial (hPCa) cells. A murine-specific AR antisense oligonucleotide (ASO) was used to suppress the expression of AR in the CAF cells. CAFs express low, but significant levels of AR relative to fibroblasts derived from non-malignant tissue. CAFs promoted growth and colony formation of hPCa cells, which was attenuated by the suppression of AR expression. Surprisingly, AR-depleted CAFs promoted increased stem cell marker expression in hPCa cells. Interferon gamma (IFN-γ) and macrophage colony-stimulating factor (M-CSF) were increased in AR-depleted CAF cells and exhibited similar effects on stem cell marker expression as seen in the CAF co-culture systems. Clinically, elevated IFN-γ expression was found to correlate with histologic grade in primary prostate cancer samples. In summary, AR and androgen-dependent signaling are active in CAFs and exert significant effects on prostate cancer cells. IFN-γ and M-CSF are AR-regulated factors secreted by CAF cells, which promote the expression of stem cell markers in prostate cancer epithelial cells. Understanding how CAFs and other constituents of stromal tissue react to anti-cancer therapies may provide insight into the development and progression of prostate cancer.

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