scholarly journals Cerebral cavernous malformation 1 determines YAP/TAZ signaling dependent metastatic hallmarks of prostate cancer cells

2020 ◽  
Author(s):  
Sangryoung Park ◽  
Ho-Yong Lee ◽  
Hansol Park ◽  
Young Seok Ju ◽  
Jayoung Kim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Cavernous Malformation ◽  
Predictive Biomarker ◽  
Cerebral Cavernous Malformation ◽  
Binding Motif ◽  
Prostate Cancer Cells ◽  
Prostate Cancer Metastasis

AbstractEnhanced 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 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 PLK1-mediated suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. We also 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. Our findings highlight the importance of CCM1-DDX5-PLK1-YAP/TAZ signaling in the metastasis of prostate cancer cells.Statement of SignificanceOur analysis of CCM1 expression and function represents a candidate predictive biomarker for prostate cancer metastasis and provides an evidence that abnormality of CCM1 can be pathogenic in prostate cancer. Importantly, CCM1 regulation of metastasis progression appears to a common molecular event in metastatic prostate cancer cells arising in disparate genetic backgrounds.

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 Crosstalk between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1083
Author(s):  
Kum Hee Noh ◽  
Ae Jin Jeong ◽  
Haeri Lee ◽  
Song-Hee Lee ◽  
Eunhee Yi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Tyrosine Phosphatase ◽  
Migration And Invasion ◽  
Metastatic Progression ◽  
Prostate Cancer Cells ◽  
Prostate Cancer Metastasis

Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs–STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.

scholarly journals SFMBT2-Mediated Infiltration of Preadipocytes and TAMs in Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2718
Author(s):  
Jungsug Gwak ◽  
Hayan Jeong ◽  
Kwanghyun Lee ◽  
Jee Yoon Shin ◽  
Taejun Sim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Down Regulation ◽  
Low Level ◽  
Potential Biomarker ◽  
Prostate Cancer Metastasis

Infiltration of diverse cell types into tumor microenvironment plays a critical role in cancer progression including metastasis. We previously reported that SFMBT2 (Scm-like with four mbt domains 2) regulates the expression of matrix metalloproteinases (MMPs) and migration and invasion of cancer cells in prostate cancer. Here we investigated whether the down-regulation of SFMBT2 regulates the infiltration of preadipocytes and tumor-associated macrophages (TAMs) in prostate cancer. We found that the down-regulation of SFMBT2 promotes the infiltration of preadipocytes and TAMs through up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression in prostate cancer. Expression of CXCL8, CCL2, CXCL10, and CCL20 was also elevated in prostate cancer patients having a higher Gleason score (≥8), which had substantially lower SFMBT2 expression. We also found that the up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression is dependent on NF-κB activation in prostate cancer cells expressing a low level of SFMBT2. Moreover, increased IL-6 from infiltrated preadipocytes and TAMs promoted migration and invasion of prostate cancer cells expressing a low level of SFMBT2. Our study may suggest that SFMBT2 a critical regulator for the infiltration of preadipocytes and TAMs into the prostate tumor microenvironment. Thus, the regulation of SFMBT2 may provide a new therapeutic strategy to inhibit prostate cancer metastasis, and SFMBT2 could be used as a potential biomarker in prostate cancer metastasis.

scholarly journals Ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT

2020 ◽  
Author(s):  
Yao Zhao ◽  
Chenchen Cai ◽  
Lubing Shi ◽  
Jiwei Wang ◽  
Miaomiao Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Eph Receptor ◽  
Prostate Cancer Metastasis

Abstract Background Ephrin-A2, a member of the Eph receptor subgroup, is used in diagnosing and determining the prognosis of prostate cancer. However, the role of ephrin-A2 in prostate cancer is still unclear. Methods We established stable clones overexpressing or silencing ephrin-A2 from prostate cancer cells. Then, CCK-8 was used in analyzing the proliferation ability of cells. CD31 staining was used in evaluating angiogenesis. Migration and invasion assay were conducted in vivo and in vitro. The expression of EMT-related markers was evaluated in prostate cancer cells through Western blotting. Results We revealed that the ectopic expression of ephrin-A2 in prostate cancer cells facilitated cell migration and invasion in vitro and promoted tumor metastasis and angiogenesis in vivo and that the silencing of ephrin-A2 completely reversed this effect. Although ephrin-A2 did not affect tumor cell proliferation in vitro, ephrin-A2 significantly promoted primary tumor growth in vivo. Furthermore, to determine the biological function of ephrin-A2, we assayed the expression of EMT-related markers in stable established cell lines. Results showed that the overexpression of ephrin-A2 in prostate cancer cells down-regulated the expression of epithelial markers (ZO-1, E-cadherin, and claudin-1) and up-regulated the expression of mesenchymal markers (N-cadherin, β-catenin, vimentin, Slug, and Snail), but the knocking out of ephrin-A2 opposed the effects on the expression of EMT markers. Conclusions These findings indicate that ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT and may be a potentially therapeutic target in metastatic prostate cancer.

scholarly journals P-REX1-Independent, Calcium-Dependent RAC1 Hyperactivation in Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 480 ◽  
Author(s):  
Martin J. Baker ◽  
Martín C. Abba ◽  
Rafael Garcia-Mata ◽  
Marcelo G. Kazanietz
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Prostate Cancer Cells ◽  
Invasive Potential ◽  
Calcium Dependent ◽  
Serum Stimulation ◽  
Alternative Means ◽  
Androgen Independent

The GTPase Rac1 is a well-established master regulator of cell motility and invasiveness contributing to cancer metastasis. Dysregulation of the Rac1 signaling pathway, resulting in elevated motile and invasive potential, has been reported in multiple cancers. However, there are limited studies on the regulation of Rac1 in prostate cancer. Here, we demonstrate that aggressive androgen-independent prostate cancer cells display marked hyperactivation of Rac1. This hyperactivation is independent of P-Rex1 activity or its direct activators, the PI3K product PIP3 and Gβγ subunits. Furthermore, we demonstrate that the motility and invasiveness of PC3 prostate cancer cells is independent of P-Rex1, supporting the analysis of publicly available datasets indicating no correlation between high P-Rex1 expression and cancer progression in patients. Rac1 hyperactivation was not related to the presence of activating Rac1 mutations and was insensitive to overexpression of a Rac-GAP or the silencing of specific Rac-GEFs expressed in prostate cancer cells. Interestingly, active Rac1 levels in these cells were markedly reduced by elevations in intracellular calcium or by serum stimulation, suggesting the presence of an alternative means of Rac1 regulation in prostate cancer that does not involve previously established paradigms.

scholarly journals How can food extracts consumed in the Mediterranean and East Asia suppress prostate cancer proliferation?

2011 ◽  
Vol 108 (3) ◽  
pp. 424-430 ◽  
Author(s):  
Mu Yao ◽  
Chanlu Xie ◽  
Maryrose Constantine ◽  
Sheng Hua ◽  
Brett D. Hambly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
East Asia ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Prostate Cancer Cells ◽  
The Mediterranean

We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferation in vitro and in vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0·8 %) for 72 h increased the percentage of cells at the G0/G1 phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2′-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation.

scholarly journals FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells

2010 ◽  
Vol 30 (5) ◽  
pp. 1243-1253 ◽  
Author(s):  
Li Ni ◽  
Chun-Song Yang ◽  
Daniel Gioeli ◽  
Henry Frierson ◽  
David O. Toft ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Feedback Loop ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Androgen Receptor Signaling ◽  
Hsp90 Chaperone ◽  
Chaperone Complex ◽  
Androgen Binding

ABSTRACT Prostate cancer progression to the androgen-independent (AI) state involves acquisition of pathways that allow tumor growth under low-androgen conditions. We hypothesized that expression of molecular chaperones that modulate androgen binding to AR might be altered in prostate cancer and contribute to progression to the AI state. Here, we report that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and describe a molecular mechanism by which FKBP51 regulates AR activity. Using recombinant proteins, we show that FKBP51 stimulates recruitment of the cochaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51-Hsp90-p23 superchaperone complex. In cells, FKBP51 expression promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding. FKBP51 stimulates androgen-dependent transcription and cell growth, and FKBP51 is part of a positive feedback loop that is regulated by AR and androgen. Finally, depleting FKBP51 levels by short hairpin RNA reduces the transcript levels of genes regulated by AR and androgen. Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells.

scholarly journals Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Yuanshen Mao ◽  
Wenfeng Li ◽  
Bao Hua ◽  
Xin Gu ◽  
Weixin Pan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Prostate Cancer Cells ◽  
Migration Inhibition ◽  
Akt Inhibitor ◽  
Phase Arrest ◽  
M Phase ◽  
And Migration

ELK3, an ETS domain-containing transcription factor, participates in various physiological and pathological processes including cell proliferation, migration, angiogenesis, and malignant progression. However, the role of ELK3 in prostate cancer cells and its mechanism are not fully understood. The contribution of ELK3 to prostate cancer progression was investigated in the present study. We showed that silencing of ELK3 by siRNA in prostate cancer cell DU145 induced S-M phase arrest, promoted apoptosis, inhibited cell proliferation and migration in vitro, and suppressed xenograft growth in mice in vivo. In accordance with its ability to arrest cells in S-M phase, the expression of cyclin A and cyclin B was downregulated. In addition, the expression of p53 was upregulated following ELK3 knockdown, while that of antiapoptotic Bcl-2 was decreased. The migration inhibition may partly due to upregulation of SERPINE1 (a serine protease inhibitor) followed ELK3 knockdown. Consistently, downregulation of SERPINE1 resulted in a modest elimination of migration inhibition resulted from ELK3 knockdown. Furthermore, we found that the AKT signaling was activated in ELK3 knockdown cells, and treatment these cells with AKT inhibitor attenuated SERPINE1 expression induced by ELK3 silencing, suggesting that activation of AKT pathway may be one of the reasons for upregulation of SERPINE1 after ELK3 knockdown. In conclusion, modulation of ELK3 expression may control the progression of prostate cancer partly by regulating cell growth, apoptosis, and migration.

An in vitro model of prostate cancer bone metastasis for highly metastatic and non-metastatic prostate cancer using nanoclay bone-mimetic scaffolds

MRS Advances ◽  
2019 ◽  
Vol 4 (21) ◽  
pp. 1207-1213 ◽  
Author(s):  
MD Shahjahan Molla ◽  
Dinesh R. Katti ◽  
Kalpana S. Katti
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Metastatic Prostate Cancer ◽  
Cancer Metastasis ◽  
Human Mesenchymal Stem Cells ◽  
Culture Technique ◽  
Complex Nature ◽  
Bone Microenvironment ◽  
Prostate Cancer Cells

ABSTRACTProstate cancer has a strong preference for metastasizing to bone which is the primary cause of prostate cancer-related morbidity and mortality. The complex nature of cancer metastasis requires the development of translational models that recapitulate a specific metastatic stage. Herein, we report the mimicking of mesenchymal to epithelial transition (MET) of prostate cancer cells using highly metastatic and a non-metastatic prostate cancer cell lines. A unique cell culture technique that we termed as ‘sequential culture’ was used to create a biomimetic bone microenvironment for metastasized prostate cancer cells by introducing bioactive factors from osteogenic induction of human mesenchymal stem cells (MSCs) within the porous 3D scaffolds. The in vitro 3D tumor model can be used as a testbed to study the interaction between prostate cancer and bone microenvironment and for the design of novel therapeutic studies.

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