scholarly journals The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

2019 ◽  
Vol 218 (6) ◽  
pp. 1943-1957 ◽  
Author(s):  
Dawid G. Nowak ◽  
Ksenya Cohen Katsenelson ◽  
Kaitlin E. Watrud ◽  
Muhan Chen ◽  
Grinu Mathew ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Genetically Engineered ◽  
Phosphatase Inhibitors ◽  
Genetically Engineered Mouse Model ◽  
Key Driver ◽  
The Common ◽  
Chromosome 16Q ◽  
Mutant Cells

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill PTEN mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.

scholarly journals Cyclocreatine suppresses prostate tumorigenesis through dual effects on SAM and creatine metabolism

2021 ◽  
Author(s):  
Rachana Patel ◽  
Lisa Rodgers ◽  
Catriona A. Ford ◽  
Linda K Rushworth ◽  
Janis Fleming ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
De Novo ◽  
Basal Respiration ◽  
Genetically Engineered ◽  
Prostate Tumorigenesis ◽  
Genetically Engineered Mouse Model ◽  
Creatine Metabolism

ABSTRACTProstate cancer is highly prevalent, being the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of PTEN and SPRY2 (Sprouty 2) tumour suppressors, we identified enhanced creatine metabolism within the phosphagen system in progressive disease. Altered creatine metabolism was validated in in vitro and in vivo prostate cancer models and in clinical cases. Upregulated creatine levels were due to increased uptake through the SLC6A8 creatine transporter and de novo synthesis, resulting in enhanced cellular basal respiration. Treatment with cyclocreatine (a creatine analogue that potently and specifically blocks the phosphagen system) dramatically reduces creatine and phosphocreatine levels. Blockade of creatine biosynthesis by cyclocreatine leads to cellular accumulation of S-adenosyl methionine (SAM), an intermediary of creatine biosynthesis, and suppresses prostate cancer growth in vitro. Furthermore, cyclocreatine treatment impairs cancer progression in our GEMM and in a xenograft liver metastasis model. Hence, by targeting the phosphagen system, cyclocreatine results in anti-tumourigenic effects from both SAM accumulation and suppressed phosphagen system.

scholarly journals Neutrophils are mediators of metastatic prostate cancer progression in bone

2020 ◽  
Vol 69 (6) ◽  
pp. 1113-1130 ◽  
Author(s):  
Diane L. Costanzo-Garvey ◽  
Tyler Keeley ◽  
Adam J. Case ◽  
Gabrielle F. Watson ◽  
Massar Alsamraae ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Prostate Cancer Progression

scholarly journals Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence

2015 ◽  
Vol 116 (4) ◽  
pp. 556-567 ◽  
Author(s):  
Mohammed Alshalalfa ◽  
Anamaria Crisan ◽  
Ismael A. Vergara ◽  
Mercedeh Ghadessi ◽  
Christine Buerki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Biochemical Recurrence ◽  
Metastatic Prostate Cancer ◽  
Genomic Analysis ◽  
Prostate Cancer Progression

scholarly journals A Splicing Variant of the Androgen Receptor Detected in a Metastatic Prostate Cancer Exhibits Exclusively Cytoplasmic Actions

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4334-4343 ◽  
Author(s):  
Monika Jagla ◽  
Marie Fève ◽  
Pascal Kessler ◽  
Gaëlle Lapouge ◽  
Eva Erdmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Dna Binding ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Splicing Variant ◽  
Activation Of Transcription

The androgen receptor (AR) is a ligand-activated transcription factor that displays genomic actions characterized by binding to androgen-response elements in the promoter of target genes as well as nongenomic actions that do not require nuclear translocation and DNA binding. In this study, we report exclusive cytoplasmic actions of a splicing variant of the AR detected in a metastatic prostate cancer. This AR variant, named AR23, results from an aberrant splicing of intron 2, wherein the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain. We show that the nuclear entry of AR23 upon dihydrotestosterone (DHT) stimulation is impaired. Alternatively, DHT-activated AR23 forms cytoplasmic and perinuclear aggregates that partially colocalize with the endoplasmic reticulum and are devoid of genomic actions. However, in LNCaP cells, this cytoplasmic DHT-activated AR23 remains partially active as evidenced by the activation of transcription from androgen-responsive promoters, the stimulation of NF-κB transcriptional activity and by the decrease of AP-1 transcriptional activity. Our data reveal novel cytoplasmic actions for this splicing AR variant, suggesting a contribution in prostate cancer progression.

scholarly journals Serum Methionine Metabolites Are Risk Factors for Metastatic Prostate Cancer Progression

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e22486 ◽  
Author(s):  
Sally Stabler ◽  
Tatsuki Koyama ◽  
Zhiguo Zhao ◽  
Magaly Martinez-Ferrer ◽  
Robert H. Allen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Cancer Progression ◽  
Metastatic Prostate Cancer ◽  
Prostate Cancer Progression

scholarly journals Genetics of Prostate Carcinoma

2021 ◽  
Vol 50 (1) ◽  
pp. 71
Author(s):  
Božo Krušlin ◽  
Lucija Škara ◽  
Tonći Vodopić ◽  
Borna Vrhovec ◽  
Jure Murgić ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Carcinoma ◽  
Poor Prognosis ◽  
Large Scale ◽  
Metastatic Prostate Cancer ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Genomic Studies ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

<p>The aim of this review is to provide a brief overview of some current approaches regarding diagnostics, pathologic features, treatment, and genetics of prostate carcinoma (PCa). Prostate carcinoma is the most common visceral tumor and the second most common cancer-related cause of death in males. Clinical outcomes for patients with localized prostate cancer are excellent, but despite advances in prostate cancer treatments, castrate-resistant prostate cancer and metastatic prostate cancer patients have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in prostate cancer. The meaning of these alterations needs to be validated in the specific prostate cancer molecular subtype context. Along these lines, there is a critical need for establishing genetically engineered mouse models, which would include speckle type BTB/POZ protein and isocitrate Dehydrogenase (NADP (+)) 1 mutant, as well as androgen receptor neuroendocrine subtypes of prostate cancer. Another urgent need is developing highly metastatic prostate cancer models, as only up to 17% of available models dis- play bone metastases and exhibit a less typical neuroendocrine prostate cancer or sarcomatoid carcinoma. Moreover, androgen deprivation and relapse should be mimicked in the genetically engineered mouse models, as androgen independence may yield a better model for metastatic castrate-resistant prostate cancer. The development of such refined animal models should be guid- ed by comparative genomics of primary versus corresponding metastatic tumors. Such an approach will have the potential to illuminate the key genetic events associated with specific molecular prostate cancer subsets and indicate directions for effective therapy.</p><p><strong>Conclusion</strong>. Despite excellent results in the treatment of localized prostatic carcinoma, castrate-resistant prostate can- cer and metastatic prostate cancer have a poor prognosis. Advanced large-scale genomic studies revealed a large number of ge- netic alterations in PCa. Experimental models of prostate carcinoma in genetically modified mice could provide new data about the genetic changes in such cancers and help in developing better animal models for treatment resistant prostate carcinomas.</p>

scholarly journals Comparative Proteomics Uncovers Correlated Signaling Network and Potential Biomarkers for Progression of Prostate Cancer

2017 ◽  
Vol 41 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Jianzhong Ai ◽  
Yi Lu ◽  
Qiang Wei ◽  
Hong Li
Keyword(s):  
Prostate Cancer ◽  
Cell Migration ◽  
Cancer Progression ◽  
Quantitative Proteomics ◽  
Tumor Metastasis ◽  
Metastatic Prostate Cancer ◽  
Bioinformatics Analysis ◽  
Mrna Level ◽  
Tumor Cell Migration ◽  
Differential Proteins

Background/Aims: Prostate cancer is one of the most common cancers for males worldwide, and it is prone to show the metastatic foci in lymph node and bone with high mortality. To date, the potential mechanism and the corresponding biomarkers for metastatic prostate cancer are still lacking. Hence, our study aims to clarify the mechanism of prostate cancer progression and identify the useful biomarkers for metastatic prostate cancer. Methods: The proteins and network tightly associated with tumor metastasis were identified using quantitative proteomics. Furthermore, the mRNA level of differential expressed proteins were confirmed using qRT-PCR, and the functional cluster analysis was performed using String and Cytoscape. Results: Totally, our study identified 203 differential proteins closely associated with tumor cell migration, and the mRNA expression of those proteins were verified by qPCR. Moreover, the migration associated molecular network was established using bioinformatics analysis. Conclusion: These data raveled the critical proteins for the cell migration of prostate cancer, and identified the potential markers for diagnosing the metastasis of prostate cancer.

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