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 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 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 Rac1b Supports Ligand-Independent Androgen Receptor Activation in Prostate Cancer Progression

2020 ◽  
pp. 1-8
Author(s):  
Gudula Schmidt ◽  
Anke Augspach ◽  
Stefanie Kowarschik ◽  
Cordula A. Jilg ◽  
Gudula Schmidt
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Receptor Activation ◽  
Genetic Alterations ◽  
Signalling Pathways ◽  
Prostate Cancer Cells ◽  
Tissue Samples ◽  
Cancer Cell Death ◽  
Androgen Independent

Prostate cancer represents one of the leading causes of morbidity and mortality of men worldwide. In precision medicine, tumors are screened for specific genetic alterations known as predictive markers for targeted therapy. In androgen-independent prostate cancer cells and in tissue samples of a prostate cancer patient treated with Goserelin, we identified the self-activating splice variant Rac1b. Importantly, the expression of Rac1b was sufficient to induce AR-dependent gene synthesis. We hypothesized that Rac1b antagonizes androgen depletion induced cancer cell death by blocking pro-apoptotic signalling pathways. In line with that selective knockdown of Rac1b or inhibition of Rac-dependent signalling pathways reinduced apoptosis in androgen-independent prostate cancer cells suggesting Rac1b inhibition as a potential novel therapeutic add on strategy against prostate cancer.

scholarly journals SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Trnski ◽  
Maja Sabol ◽  
Sanja Tomić ◽  
Ivan Štefanac ◽  
Milanka Mrčela ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Therapy Resistance ◽  
Androgen Deprivation ◽  
Prostate Cancer Cells ◽  
Androgen Independence ◽  
Androgen Receptor Activity ◽  
Signaling Activation ◽  
Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

scholarly journals CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. VOLUME 283 (2008) PAGES 10162-10173

2008 ◽  
Vol 283 (28) ◽  
pp. 19872
Author(s):  
Florian Gackière ◽  
Gabriel Bidaux ◽  
Philippe Delcourt ◽  
Fabien Van Coppenolle ◽  
Maria Katsogiannou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Calcium Channels ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Calcium Dependent ◽  
Neuroendocrine Prostate Cancer

scholarly journals Caveolae Contribute to the Apoptosis Resistance Induced by the α1A-Adrenoceptor in Androgen-Independent Prostate Cancer Cells

PLoS ONE ◽  
2009 ◽  
Vol 4 (9) ◽  
pp. e7068 ◽  
Author(s):  
Maria Katsogiannou ◽  
Charbel El Boustany ◽  
Florian Gackiere ◽  
Philippe Delcourt ◽  
Anne Athias ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Apoptosis Resistance ◽  
Androgen Independent

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.

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