Identification of a Wells–Dawson polyoxometalate-based AP-2γ inhibitor with pro-apoptotic activity

2018 ◽  
Vol 475 (11) ◽  
pp. 1965-1977 ◽  
Author(s):  
Jiamiao Hu ◽  
Si Kee Tan ◽  
Michelle Gek Liang Lim ◽  
Shie Hong Chang ◽  
Guimei Cui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecule ◽  
Cancer Biology ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Molecule Inhibitor ◽  
Direct Binding ◽  
Dawson Structure ◽  
Apoptotic Activity ◽  
Apoptotic Effects

AP-2 gamma (AP-2γ) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2γ, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells–Dawson structure K6[P2Mo18O62] (Dawson-POM) that blocks the DNA-binding activity of AP-2γ. We showed that this blocking activity is due to the direct binding of Dawson-POM to AP-2γ. We also provided evidence to show that Dawson-POM decreases AP-2γ-dependent transcription similar to silencing the gene. Finally, we demonstrated that Dawson-POM contains anti-proliferative and pro-apoptotic effects in breast cancer cells. In summary, we identified the first small molecule inhibitor of AP-2γ and showed Dawson-POM-mediated inhibition of AP-2γ as a potential avenue for cancer therapy.

scholarly journals Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity

2005 ◽  
Vol 65 (19) ◽  
pp. 9047-9055 ◽  
Author(s):  
Dehe Kong ◽  
Eun Jung Park ◽  
Andrew G. Stephen ◽  
Maura Calvani ◽  
John H. Cardellina ◽  
...  
Keyword(s):  
Dna Binding ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Small Molecule Inhibitor ◽  
Binding Activity ◽  
Hypoxia Inducible Factor 1 ◽  
Dna Binding Activity ◽  
Molecule Inhibitor

Effects of Echinomycin on PCNA-Dependent Follicular Development in PMSG-Induced Sprague-Dawley Rats

2014 ◽  
Vol 998-999 ◽  
pp. 228-232
Author(s):  
Zheng Hong Zhang ◽  
Fan Wang ◽  
Yan Qing Wu ◽  
Zong Hao Tang ◽  
Qing Qiang Lin ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Follicular Development ◽  
Antral Follicle ◽  
Binding Activity ◽  
Nuclear Antigen ◽  
Sprague Dawley ◽  
Dna Binding Activity ◽  
Molecule Inhibitor ◽  
Protein Expressions ◽  
Serum Gonadotropin

Echinomycin (Ech) is a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity, which plays a crucial role in the regulation of ovarian functions in mammals. The present study was designed to test the hypothesis that hypoxia-inducible factor (HIF)-1alpha-mediated proliferation cell nuclear antigen (PCNA) expressions contributed to the follicular development in the rat ovary primed by pregnant mare serum gonadotropin (PMSG). Through the histological examination, the decrease of growing and antral follicle numbers was found after Ech treatment both in control and PMSG treated groups. And then PCNA mRNA and protein expressions were found to significantly increase in the ovaries treated with PMSG, and the similar changes were found in HIF-1alpha mRNA and protein expressions, indicating PMSG-induced follicular development may be through HIF-1alpha/PCNA signaling. Furthermore, PCNA expression was found to significantly decrease in the ovaries after Ech treatment, while HIF-1alpha mRNA and protein expression was no obviously changes. Further analysis found the changes of PCNA expression were consistent with HIF-1 activity in the ovaries, further suggesting the regulatory roles in the follicular development. Taken together, these results demonstrated this HIF-1alpha-mediated PCNA expression is one of the important mechanisms regulating the ovarian follicular development in mammals. Keywords: HIF-1alpha; PCNA; echinomycin; HIF prolyl hyodroxylase acitvity; follicular development

scholarly journals Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis

2020 ◽  
Vol 488 ◽  
pp. 27-39 ◽  
Author(s):  
Ryan T. Bishop ◽  
Silvia Marino ◽  
Giovana Carrasco ◽  
Boya Li ◽  
Richard J. Allen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecule ◽  
Skeletal Metastasis ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Combined Administration

scholarly journals Constitutive nuclear NFκB/rel DNA-binding activity of rat thymocytes is increased by stimuli that promote apoptosis, but not inhibited by pyrrolidine dithiocarbamate

1995 ◽  
Vol 312 (3) ◽  
pp. 833-838 ◽  
Author(s):  
A F G Slater ◽  
M Kimland ◽  
S A Jiang ◽  
S Orrenius
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Gradient Centrifugation ◽  
Binding Activity ◽  
Pyrrolidine Dithiocarbamate ◽  
Nf Kappa B ◽  
Dna Binding Activity ◽  
Apoptotic Activity

Rat thymocytes spontaneously undergo apoptotic death in cell culture, and are also sensitive to the induction of apoptosis by various stimuli. We show that unstimulated thymocytes constitutively express a p50-containing nuclear factor kappa B (NF kappa B)/rel DNA-binding activity in their nuclei. When the cells were fractionated by density-gradient centrifugation this activity was found to be most pronounced in immature CD4+8+ thymocytes, the cell population that undergoes selection by apoptosis in vivo and that is most sensitive to external inducers of apoptosis in vitro. The intensity of the NF kappa B/rel protein-DNA complex was significantly enhanced 30 min after exposing thymocytes to methylprednisolone or etoposide, two agents well known to induce apoptosis in these cells. Expression of this DNA-binding activity therefore correlates with the subsequent occurrence of apoptosis. By analogy to other systems, it has been suggested that antioxidants such as pyrrolidine dithiocarbamate (PDTC) inhibit thymocyte apoptosis by preventing the activation of an NF kappa B/rel transcription factor. However, we have found that etoposide induces a very similar enhancement of the NF kappa B/rel DNA-binding activity in the presence or absence of PDTC, despite a pronounced inhibition of apoptotic DNA fragmentation in the former situation. Dithiocarbamates therefore do not exert their anti-apoptotic activity in thymocytes by inhibiting the activation of this transcription factor.

scholarly journals Chemokines modulate glycan binding and immunoregulatory activity of galectins

2021 ◽  
Author(s):  
Lucia Sanjurjo ◽  
Iris Schulkens ◽  
Pauline Touarin ◽  
Roy Heusschen ◽  
Ed Aanhane ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Binding Activity ◽  
Carbohydrate Binding ◽  
Peripheral Blood Mononuclear ◽  
Cytokines And Chemokines ◽  
Direct Binding ◽  
Apoptotic Activity

Abstract Galectins are versatile glycan-binding proteins involved in immunomodulation. Increasing evidence suggests that galectins can control the immunoregulatory function of cytokines and chemokines through direct binding. Here, we report a new inverse mechanism by which chemokines control the immunomodulatory function of galectins. In a galectin-chemokine interaction screen we identified several specific galectin-chemokine binding pairs, including galectin-1/CXCL4. NMR analyses showed that CXCL4 binds on the surface edge of the galectin-1 ß-sheet causing changes in the galectin-1 carbohydrate binding site. Consequently, the interaction with CXCL4 altered the glycan binding affinity and specificity of galectin-1. With regard to immunomodulation, CXCL4 potentiated the apoptotic activity of galectin-1 on activated peripheral blood mononuclear cells. The potentiation of apoptosis specifically affected CD8+ T cells, while no effect was observed in CD4+ T cells. An opposite regulatory activity was found for another galectin-chemokine pair, i.e., galectin-9/CCL5. While CCL5 reduced the apoptosis induction by galectin-9 in activated PBMCs, this was only statistically significant for CD4+ T cells and not for CD8+ T cells. Collectively, the current study describes a novel immunomodulatory mechanism in which specific galectin-chemokine interactions control the glycan-binding activity and immunoregulatory function of galectins.

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