scholarly journals A balancing act: PHLPP2 fine tunes AKT activity and MYC stability in prostate cancer

2019 ◽  
Vol 218 (6) ◽  
pp. 1771-1772 ◽  
Author(s):  
Roxanne Toivanen ◽  
Luc Furic
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Disease Progression ◽  
Prostate Tumor ◽  
Pten Loss ◽  
Akt Activation ◽  
Cell Biol

PTEN loss stimulates prostate tumor progression by sustaining AKT activation. Nowak et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201902048) surprisingly show that the AKT-suppressing phosphatase PHLPP2 promotes disease progression in the context of dual PTEN and p53 loss by increasing MYC stability.

The secreted matrix protein mindin increases prostate tumor progression and tumor-bone crosstalk via ERK 1/2 regulation

2019 ◽  
Vol 40 (7) ◽  
pp. 828-839
Author(s):  
Juan A Ardura ◽  
Irene Gutiérrez-Rojas ◽  
Luis Álvarez-Carrión ◽  
M Rosario Rodríguez-Ramos ◽  
José M Pozuelo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Matrix Protein ◽  
Bone Cells ◽  
Prostate Tumor ◽  
Dependent Manner ◽  
Prostate Tumors ◽  
Adenocarcinoma Cells ◽  
Prostate Tumor Cells

Abstract Advanced prostate cancer cells preferentially metastasize to bone by acquiring a bone phenotype that allows metastatic cells to thrive in the skeletal environment. Identification of factors that promote the expression of ectopic bone genes—process known as osteomimicry—leading to tumor progression is crucial to prevent and treat metastatic prostate cancer and prolong life expectancy for patients. Here, we identify the extracelular matrix protein mindin in the secretome of prostate adenocarcinoma cells and show that mindin overexpression in human and mouse TRAMP-C1-induced prostate tumors correlates with upregulated levels of bone-related genes in the tumorigenic prostate tissues. Moreover, mindin silencing decreased osteomimicry in adenocarcinoma cells and in the prostate tumor mice model, as well as reduced tumor cell proliferation, migration and adhesion to bone cells. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation decreased the proliferative, migratory and pro-adhesion actions of mindin on prostate tumor cells. In addition, conditioned media obtained by crosstalk stimulation of either osteocytes or osteoblasts with the secretome of TRAMP-C1 cells promoted osteomimicry in prostate tumor cells; an effect inhibited by mindin silencing of TRAMP-C1 cells. In vivo, tibiae of primary tumor-bearing mice overexpressed the pro-angiogenic and pro-metastattic factor vascular endothelial growth factor receptor 2 (VEGFR2) in a mindin-dependent manner. Our findings indicate that mindin is a novel regulator of osteomimicry in prostate tumors and potentially mediates tumor-bone cell crosstalk, suggesting its promising role as a target to inhibit bone metastases.

scholarly journals Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1071 ◽  
Author(s):  
Juan A. Ardura ◽  
Luis Álvarez-Carrión ◽  
Irene Gutiérrez-Rojas ◽  
Verónica Alonso
Keyword(s):  
Prostate Cancer ◽  
Calcium Channels ◽  
Calcium Signaling ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Calcium Binding ◽  
Transient Receptor Potential ◽  
Prostate Tumor ◽  
Tumor Cell Death ◽  
Prostate Cancers

Advanced prostate cancers that progress to tumor metastases are often considered incurable or difficult to treat. The etiology of prostate cancers is multi-factorial. Among other factors, de-regulation of calcium signals in prostate tumor cells mediates several pathological dysfunctions associated with tumor progression. Calcium plays a relevant role on tumor cell death, proliferation, motility-invasion and tumor metastasis. Calcium controls molecular factors and signaling pathways involved in the development of prostate cancer and its progression. Such factors and pathways include calcium channels and calcium-binding proteins. Nevertheless, the involvement of calcium signaling on prostate cancer predisposition for bone tropism has been relatively unexplored. In this regard, a diversity of mechanisms triggers transient accumulation of intracellular calcium in prostate cancer cells, potentially favoring bone metastases development. New therapies for the treatment of prostate cancer include compounds characterized by potent and specific actions that target calcium channels/transporters or pumps. These novel drugs for prostate cancer treatment encompass calcium-ATPase inhibitors, voltage-gated calcium channel inhibitors, transient receptor potential (TRP) channel regulators or Orai inhibitors. This review details the latest results that have evaluated the relationship between calcium signaling and progression of prostate cancer, as well as potential therapies aiming to modulate calcium signaling in prostate tumor progression.

scholarly journals Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Disharee Nath ◽  
Xiang Li ◽  
Claudia Mondragon ◽  
Dawn Post ◽  
Ming Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wnt Signaling ◽  
Tumor Progression ◽  
Cell Line ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Adaptor Protein ◽  
Prostate Tumor ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

Abstract Background Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, acts as tumor suppressor in prostate cancer but the role of ABI1 in EMT is not clear. Methods To investigate the molecular mechanism by which loss of ABI1 contributes to tumor progression, we disrupted the ABI1 gene in the benign prostate epithelial RWPE-1 cell line and determined its phenotype. Levels of ABI1 expression in prostate organoid tumor cell lines was evaluated by Western blotting and RNA sequencing. ABI1 expression and its association with prostate tumor grade was evaluated in a TMA cohort of 505 patients and metastatic cell lines. Results Low ABI1 expression is associated with biochemical recurrence, metastasis and death (p = 0.038). Moreover, ABI1 expression was significantly decreased in Gleason pattern 5 vs. pattern 4 (p = 0.0025) and 3 (p = 0.0012), indicating an association between low ABI1 expression and highly invasive prostate tumors. Disruption of ABI1 gene in RWPE-1 cell line resulted in gain of an invasive phenotype, which was characterized by a loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 spheroids. Through RNA sequencing and protein expression analysis, we discovered that ABI1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of ABI1. Furthermore, an increase in STAT3 phosphorylation upon ABI1 inactivation and the evidence of a high-affinity interaction between the FYN SH2 domain and ABI1 pY421 support a model in which ABI1 acts as a gatekeeper of non-canonical WNT-EMT pathway activation downstream of the FZD2 receptor. Conclusions ABI1 controls prostate tumor progression and epithelial plasticity through regulation of EMT-WNT pathway. Here we discovered that ABI1 inhibits EMT through suppressing FYN-STAT3 activation downstream from non-canonical WNT signaling thus providing a novel mechanism of prostate tumor suppression.

scholarly journals EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marita Zoma ◽  
Laura Curti ◽  
Dheeraj Shinde ◽  
Domenico Albino ◽  
Abhishek Mitra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Target Genes ◽  
Genetically Engineered ◽  
Post Translational Modification ◽  
Pten Loss ◽  
Genetically Engineered Mouse Model ◽  
Oncogenic Activity ◽  
Domain Interactions ◽  
Prostate Cancers

AbstractThe TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Ptenflox/floxRosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.

scholarly journals Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marco Bolis ◽  
Daniela Bossi ◽  
Arianna Vallerga ◽  
Valentina Ceserani ◽  
Manuela Cavalli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Single Cell ◽  
Disease Progression ◽  
Macrophage Polarization ◽  
Driver Mutations ◽  
M2 Macrophage ◽  
Web Resource ◽  
Cancer Transcriptome ◽  
Genomic Studies

AbstractComprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory – reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.

Characteristics of Chinese patients with advanced prostate cancer: A muliticentre, non-interventional, observational, prospective, registry study of docetaxel.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 328-328
Author(s):  
Dalin He ◽  
Zhongquan Sun ◽  
Jianming Guo ◽  
Zhigen Zhang ◽  
Yuxi Shan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
Disease Progression ◽  
Remission Rate ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
Chinese Patients ◽  
Second Line ◽  
Registry Study ◽  
First Line

328 Background: Prostate cancer (PC) is the second most frequently diagnosed malignancy in males worldwide, and stands in 7th place among malignancies in Chinese males. This study investigated the real-world treatment patterns of docetaxel as chemotherapy in patients with advanced PC in China. Methods: This was a multi-center, prospective, observational, non-interventional, product registry study. All patients with advanced PC who failed with previous endocrine therapies, were receiving docetaxel containing chemotherapy, and consented to participate in the study were eligible to be enrolled. Patients were followed-up 2 years, for the collection and analysis of data on docetaxel treatment mode, prostate specific antigen (PSA) remission rate, survival time, etc. Results: A total of 407 patients were enrolled from Aug 2011 through Jun 2014, with a mean Gleason score of 8.0 (SD: 1.11), and median PSA of 61.0 (range: 0.0 to 5000.0) ng/ml. 302 (74.2%) patients were classified as clinical stage IV. For Eastern Cooperative Oncology Group (ECOG) score, 145 (35.6%), 205 (50.4%), 48 (11.8%), patients had scores of 0, 1, 2, respectively. Metastasis to bone was present in 340 (83.5%) patients; metastasis to other organs (liver, lungs, adrenal glands, brain, etc.) was present in 57 (14.0%) patients. Last disease progression prior to enrolment was evidenced by tumor progression in 132 (32.4%) patients and by PSA elevation in 379 (93.1%) patients. 173 (43.0%) and 120 (29.9%) patients started docetaxel therapy after failure of the first line and second line endocrine therapies, respectively; 51 (12.7%) patients after failure of the third line or more endocrine therapies. Conclusions: This abstract presented characteristics of Chinese patients with advanced PC revealed by a Chinese PC study, which indicated Chinese patients were in later stage and higher risk compared with their western counterparts. The majority of patients started docetaxel therapy after failure of first line and second line endocrine therapies. PSA elevation and tumor progression were the 2 main causes that Urologists determined for disease progression. Clinical trial information: no registration number.

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