scholarly journals Histone Deacetylase Inhibitors Increase p27Kip1by Affecting Its Ubiquitin-Dependent Degradation through Skp2 Downregulation

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Adriana Borriello ◽  
Silvio Naviglio ◽  
Debora Bencivenga ◽  
Ilaria Caldarelli ◽  
Annunziata Tramontano ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Posttranslational Modifications ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitor ◽  
Protein Levels ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Skp2 Protein ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds

Histone deacetylase inhibitors (HDACIs) represent an intriguing class of pharmacologically active compounds. Currently, some HDACIs are FDA approved for cancer therapy and many others are in clinical trials, showing important clinical activities at well tolerated doses. HDACIs also interfere with the aging process and are involved in the control of inflammation and oxidative stress.In vitro, HDACIs induce different cellular responses including growth arrest, differentiation, and apoptosis. Here, we evaluated the effects of HDACIs on p27Kip1, a key cyclin-dependent kinase inhibitor (CKI). We observed that HDACI-dependent antiproliferative activity is associated with p27Kip1accumulation due to a reduced protein degradation. p27Kip1removal requires a preliminary ubiquitination step due to the Skp2-SCF E3 ligase complex. We demonstrated that HDACIs increase p27Kip1stability through downregulation of Skp2 protein levels. Skp2 decline is only partially due to a reduced Skp2 gene expression. Conversely, the protein decrease is more profound and enduring compared to the changes of Skp2 transcript. This argues for HDACIs effects on Skp2 protein posttranslational modifications and/or on its removal. In summary, we demonstrate that HDACIs increase p27Kip1by hampering its nuclear ubiquitination/degradation. The findings might be of relevance in the phenotypic effects of these compounds, including their anticancer and aging-modulating activities.

scholarly journals The Impact of Cand1 in Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 428
Author(s):  
Andrea Eigentler ◽  
Piotr Tymoszuk ◽  
Johanna Zwick ◽  
Arndt A. Schmitz ◽  
Andreas Pircher ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Clinical Findings ◽  
Protein Levels ◽  
Bioinformatic Tools ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Genes Encoding ◽  
The Impact

Evidence has accumulated asserting the importance of cullin-RING (really interesting new gene) ubiquitin ligases (CRLs) and their regulator Cullin-associated neural-precursor-cell-expressed developmentally down-regulated 8 (NEDD8) dissociated protein 1 (Cand1) in various cancer entities. However, the role of Cand1 in prostate cancer (PCa) has not been intensively investigated so far. Thus, in the present study, we aimed to assess the relevance of Cand1 in the clinical and preclinical setting. Immunohistochemical analyses of radical prostatectomy specimens of PCa patients showed that Cand1 protein levels are elevated in PCa compared to benign areas. In addition, high Cand1 levels were associated with higher Gleason Scores, as well as higher tumor recurrence and decreased overall survival. In line with clinical findings, in vitro experiments in different PCa cell lines revealed that knockdown of Cand1 reduced cell viability and proliferation and increased apoptosis, therefore underlining its role in tumor progression. We also found that the cyclin-dependent kinase inhibitor p21 is significantly upregulated upon downregulation of Cand1. Using bioinformatic tools, we detected genes encoding for proteins linked to mRNA turnover, protein polyubiquitination, and proteasomal degradation to be significantly upregulated in Cand1high tumors. Next generation sequencing of PCa cell lines resistant to the anti-androgen enzalutamide revealed that Cand1 is mutated in enzalutamide-resistant cells, however, with little functional and clinically relevant impact in the process of resistance development. To summarize the present study, we found that high Cand1 levels correlate with PCa aggressiveness.

scholarly journals HJURP promotes proliferation in prostate cancer cells through increasing CDKN1A degradation via the GSK3β/JNK signaling pathway

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Wenjie Lai ◽  
Weian Zhu ◽  
Chutian Xiao ◽  
Xiaojuan Li ◽  
Yu Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Protein Levels ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Recognition Protein ◽  
Cancer Types

AbstractGenes with cross-cancer aberrations are most likely to be functional genes or potential therapeutic targets. Here, we found a total of 137 genes were ectopically expressed in eight cancer types, of which Holliday junction recognition protein (HJURP) was significantly upregulated in prostate cancer (PCa). Moreover, patients with higher HJURP mRNA and protein levels had poorer outcomes, and the protein levels served as an independent prognosis factor for the overall survival of PCa patients. Functionally, ectopic HJURP expression promoted PCa cells proliferation in vitro and in vivo. Mechanistically, HJURP increased the ubiquitination of cyclin-dependent kinase inhibitor 1 (CDKN1A) via the GSK3β/JNK signaling pathway and decreased its stability. This study investigated the role of HJURP in PCa proliferation and may provide a novel prognostic and therapeutic target for PCa.

scholarly journals Marine-Derived Compounds with Anti-Alzheimer’s Disease Activities

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 410
Author(s):  
Salar Hafez Ghoran ◽  
Anake Kijjoa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Thinking Skills ◽  
Mechanisms Of Action ◽  
Brain Disorder ◽  
Brain Functioning ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds

Alzheimer’s disease (AD) is an irreversible and progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to perform simple tasks. As the aging population continues to increase exponentially, AD has become a big concern for society. Therefore, neuroprotective compounds are in the spotlight, as a means to tackle this problem. On the other hand, since it is believed—in many cultures—that marine organisms in an individual diet cannot only improve brain functioning, but also slow down its dysfunction, many researchers have focused on identifying neuroprotective compounds from marine resources. The fact that the marine environment is a rich source of structurally unique and biologically and pharmacologically active compounds, with unprecedented mechanisms of action, marine macroorganisms, such as tunicates, corals, sponges, algae, as well as microorganisms, such as marine-derived bacteria, actinomycetes, and fungi, have been the target sources of these compounds. Therefore, this literature review summarizes and categorizes various classes of marine-derived compounds that are able to inhibit key enzymes involved in AD, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE-1), and different kinases, together with the related pathways involved in the pathogenesis of AD. The compounds discussed herein are emerging as promising anti-AD activities for further in-depth in vitro and in vivo investigations, to gain more insight of their mechanisms of action and for the development of potential anti-AD drug leads.

Anti-tumoral efficiacy of four different histone deacetylase inhibitors on hepatoma cells in vitro

2003 ◽  
Vol 38 ◽  
pp. 95
Author(s):  
M. Ganslmayer ◽  
C. Herold ◽  
M. Ocker ◽  
S. Zopf ◽  
S. Kareth ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hepatoma Cells

In vitro antitumor mechanism of a novel cyclin-dependent kinase inhibitor CDKI-83

2011 ◽  
Vol 30 (3) ◽  
pp. 889-897 ◽  
Author(s):  
Xiangrui Liu ◽  
Frankie Lam ◽  
Shenhua Shi ◽  
Peter M. Fischer ◽  
Shudong Wang
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor

scholarly journals NEW PHARMACOLOGICALLY ACTIVE COMPOUNDS BASED ON 5-HYDROXY-7-METHOXY-2-PHENYLCHROMAN-4-ONE

2021 ◽  
Vol 3 ◽  
pp. 119-127
Author(s):  
G.M. Baisarov ◽  
◽  
S.M. Adekenov ◽  
Keyword(s):  
Nmr Spectroscopy ◽  
13C Nmr ◽  
Potassium Carbonate ◽  
13C Nmr Spectroscopy ◽  
1H And 13C Nmr ◽  
Pharmacologically Active ◽  
Pharmacologically Active Compounds ◽  
First Time

The reaction of 5-hydroxy-7-methoxy-2-phenylchroman-4-one with dibromoalkanes in acetone in the presence of potassium carbonate proceeds according to the Michael’s retro-reaction O-alkylation and leads to the formation of the corresponding 2-(bromo-alkoxy) chalcones. The structure of the synthesized compounds was confirmed by IR-, 1H- and 13C-NMR spectroscopy. The cytotoxic, hepatoprotective and anti-inflammatory effects of chalcone derivatives (2-3) were studied for the first time in vitro and in vivo.

scholarly journals Identification of brain metastasis genes and therapeutic evaluation of histone deacetylase inhibitors in a clinically relevant model of breast cancer brain metastasis

2018 ◽  
Author(s):  
Soo-Hyun Kim ◽  
Richard P. Redvers ◽  
Lap Hing Chi ◽  
Xiawei Ling ◽  
Andrew J. Lucke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Brain Metastasis ◽  
Histone Deacetylase ◽  
Clinical Relevance ◽  
Histone Deacetylase Inhibitors ◽  
Novel Therapies ◽  
Breast Cancer Brain Metastasis ◽  
The Brain

ABSTRACTBreast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.SUMMARY STATEMENTWe introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis and test novel therapies.

Sign in / Sign up

Export Citation Format

Share Document