scholarly journals Frequent discordance betweenERGgene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer

The Prostate ◽  
2014 ◽  
Vol 74 (12) ◽  
pp. 1199-1208 ◽  
Author(s):  
Aaron M. Udager ◽  
Yang Shi ◽  
Scott A. Tomlins ◽  
Ajjai Alva ◽  
Javed Siddiqui ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Rapid Autopsy

scholarly journals Imipramine Inhibits Migration and Invasion in Metastatic Castration-Resistant Prostate Cancer PC-3 Cells via AKT-Mediated NF-κB Signaling Pathway

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4619
Author(s):  
Eun Yeong Lim ◽  
Joon Park ◽  
Yun Tai Kim ◽  
Min Jung Kim
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Castration Resistant Prostate Cancer ◽  
Monocyte Chemoattractant Protein 1 ◽  
Downstream Signaling ◽  
Castration Resistant

Imipramine (IMI) is a tricyclic synthetic antidepressant that is used to treat chronic psychiatric disorders, including depression and neuropathic pain. IMI also has inhibitory effects against various cancer types, including prostate cancer; however, the mechanism of its anticancer activity is not well understood. In the present study, we investigated the antimetastatic and anti-invasive effects of IMI in metastatic castration-resistant prostate cancer PC-3 cells, with an emphasis on the serine/threonine protein kinase AKT-mediated nuclear factor kappa B (NF-κB) signaling pathway. While IMI did not induce cell death, it attenuated PC-3 cell proliferation. According to the wound healing assay and invasion assay, migration and invasion in PC-3 cells were significantly inhibited by IMI in a dose-dependent manner. IMI significantly downregulated p-AKT protein expression but upregulated phospho-extracellular signal-regulated kinase (ERK1)/2 protein expression levels. Furthermore, IMI treatment resulted in decreased AKT-mediated downstream signaling, including p-inhibitor of κB kinase (IKK)α/β, p-inhibitor of κB (IκBα), and p-p65. Inhibited NF-κB signaling reduced the secretion of several proinflammatory cytokines and chemokine by PC-3 cells. Overall, our study explored the negative correlation between the use of antidepressants and prostate cancer progression, showing that IMI attenuated cell viability, migration, and invasion of PC-3 cells by suppressing the expression of AKT and NF-κB-related signaling proteins and secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1).

scholarly journals ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer

2014 ◽  
Vol 17 (2) ◽  
pp. 126-131 ◽  
Author(s):  
J R Gsponer ◽  
M Braun ◽  
V J Scheble ◽  
T Zellweger ◽  
A Bachmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Erg Rearrangement

scholarly journals Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1167-1179
Author(s):  
David R. Wise ◽  
Jeffrey A. Schneider ◽  
Joshua Armenia ◽  
Victor Adorno Febles ◽  
Bridget McLaughlin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wnt Signaling ◽  
Nk Cells ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dkk1 Expression ◽  
Rapid Autopsy ◽  
Dickkopf 1

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

scholarly journals Targeting ADT-Induced Activation of the E3 Ubiquitin Ligase Siah2 to Delay the Occurrence of Castration-Resistant Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Tingmang Yan ◽  
Dapeng Zhou ◽  
Youwei Shi ◽  
Di Cui ◽  
Juntao Jiang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Castration Resistant Prostate Cancer ◽  
Vitamin K3 ◽  
Protein Levels ◽  
Castration Resistant

Siah2 is an E3 ubiquitin ligase that targets androgen receptor (AR) and plays an important role in the development of castration-resistant prostate cancer (CRPC). However, the regulation of Siah2 in prostate cancer (PCa) is largely unknown. In this study, we used AR-dependent and -independent cells lines to investigate the cellular roles of AR and androgen deprivation therapy (ADT) on Siah2 protein levels and E3 ligase activity using Western blotting and co-immunoprecipitation. We also validated our findings using patient samples taken before and after ADT. Finally, we used xenograft tumor models to test the effects of ADT combined with vitamin K3 (Vit K3) on tumor growth in vivo. Our results showed that AR stabilizes Siah2 protein by attenuating its self-ubiquitination and auto-degradation, likely by blocking its E3 ubiquitin ligase activity. Conversely, ADT decreased Siah2 protein expression but enhanced its E3 ligase activity in PCa cells. Notably, the findings that ADT decreasing Siah2 protein expression were verified in a series of paired PCa samples from the same patient. Additionally, we found that ADT-induced Siah2 activation could be abolished by Vit K3. Strikingly, ADT combined with Vit K3 treatment delayed the occurrence of CRPC and dramatically inhibited the growth of tumor xenografts compared with ADT treatment alone. AR is an inhibitor of Siah2 in PCa, and ADT leads to the continuous activation of Siah2, which may contribute to CRPC. Finally, ADT+Vit K3 may be a potential approach to delay the occurrence of CRPC.

Single-lesion PSMA protein expression and response to Lu-177 PSMA therapy in patients with castration-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5065-5065
Author(s):  
Judith Stangl-Kremser ◽  
Sazan Rasul ◽  
Jeffrey J. Tosoian ◽  
Simpa Salami ◽  
Alexander Zaslavsky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Pet Imaging ◽  
Metastatic Tumor ◽  
Specific Response ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Tumor Tissues ◽  
Psma Pet ◽  
Psma Expression

5065 Background: The recent introduction of Lu-177 PSMA for the treatment of castration-resistant prostate cancer (CRPC) has been met with much excitement. Initial reports of clinical response are promising, despite known inter- and intra-patient molecular heterogeneity. In this study, we examined the utility of PSMA protein expression in metastatic tumor tissues as a predictor of lesion-specific response to Lu-177 PSMA therapy in men with CRPC. Methods: Between 2015-2020, 19 patients with metastases at multiple sites underwent metastatic lesion biopsy, Ga-68 PSMA PET imaging, and subsequent treatment with three cycles of Lu-177 PSMA. A monoclonal anti-PSMA antibody (EPITOMICS (USA), 1:50) was used to semi-quantitatively assess PSMA protein expression in the biopsy specimen. The histoscore (range 0-300) was derived from intensity and extent of the immunohistochemistry staining and was determined by experienced genitourinary pathologists. Imaging evaluation was performed according to the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria. We assessed the association of the PSMA protein expression in metastatic tumor tissues and the lesion-specific response to Lu-177 PSMA therapy. Results: In 12 patients with biopsy specimens available for staining, PSMA expression correlated with enhancement (SUVmax) of the biopsy site on Ga-68 PSMA PET imaging (rs = 0.63). Of the nine patients with repeat imaging after Lu-177 PSMA therapy, five (55.6%) had a lesion-specific response at the site of biopsy. PSMA expression on immunohistochemistry was unable to accurately predict lesion-specific response in univariable analysis (p = 0.81, 95% CI 94.6-76.6). Among the five men with a lesion-specific response, three (60%) experienced overall progression based on PERCIST. There was no association between lesion-specific response and overall progression (p = 0.64). Conclusions: In patients with multiple metastases, PSMA protein expression from a single site biopsy was not predictive of site-specific Lu-177 PSMA response based on PERCIST. Additional studies are necessary to further interrogate the clinical consequence of PSMA expression heterogeneity in metastatic sites as well as the mechanisms underpinning resistance to Lu-177 PSMA in patients with CRPC.

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