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 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 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.

scholarly journals Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

2018 ◽  
Vol 47 (2) ◽  
pp. 759-773 ◽  
Author(s):  
SongTao Xiang ◽  
PeiLiang Zou ◽  
JingJing Wu ◽  
Fang Zheng ◽  
Qing Tang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Cycle Distribution ◽  
Muc1 Expression ◽  
Castration Resistant Prostate Cancer ◽  
Antitumor Effects ◽  
Castration Resistant ◽  
Muc1 Gene

Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

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