scholarly journals Anti-tumor effects of an ID antagonist with no observed acquired resistance

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Paulina M. Wojnarowicz ◽  
Marta Garcia Escolano ◽  
Yun-Han Huang ◽  
Bina Desai ◽  
Yvette Chin ◽  
...  
Keyword(s):  
Mouse Models ◽  
Colorectal Neoplasia ◽  
Acquired Resistance ◽  
Binding Pocket ◽  
Tumor Burden ◽  
Ocular Neovascularization ◽  
Helix Loop Helix ◽  
Id Proteins ◽  
Cell Growth And Viability ◽  
Hlh Transcription Factors

AbstractID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.

scholarly journals Anti-tumor effects of an Id antagonist with no acquired resistance

2020 ◽  
Author(s):  
Paulina M. Wojnarowicz ◽  
Marta Garcia Escolano ◽  
Yun-Han Huang ◽  
Bina Desai ◽  
Yvette Chin ◽  
...  
Keyword(s):  
Mouse Models ◽  
Protein Interactions ◽  
Colorectal Neoplasia ◽  
Acquired Resistance ◽  
Binding Pocket ◽  
Tumor Burden ◽  
Protein Protein Interactions ◽  
Ocular Neovascularization ◽  
Helix Loop Helix ◽  
Id Proteins

SummaryId proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket and efficient degradation of the Id proteins. Thus, AGX51 is a first-in-class compound that antagonizes Id proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.

scholarly journals Id2 Promotes Apoptosis by a Novel Mechanism Independent of Dimerization to Basic Helix-Loop-Helix Factors

1998 ◽  
Vol 18 (9) ◽  
pp. 5435-5444 ◽  
Author(s):  
Monica Florio ◽  
Maria-Clemencia Hernandez ◽  
Hui Yang ◽  
Hui-Kuo Shu ◽  
John L. Cleveland ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Target Genes ◽  
Specific Binding ◽  
Helix Loop Helix ◽  
Cell Death Pathway ◽  
Id Proteins ◽  
Enhanced Expression ◽  
Positive Regulators ◽  
Hlh Transcription Factors

ABSTRACT Members of the helix-loop-helix (HLH) family of Id proteins have demonstrated roles in the regulation of differentiation and cell proliferation. Id proteins inhibit differentiation by HLH-mediated heterodimerization with basic HLH transcription factors. This blocks their sequence-specific binding to DNA and activation of target genes that are often expressed in a tissue-specific manner. Id proteins can also act as positive regulators of cell proliferation. The different mechanisms proposed for Id-mediated promotion of entry into S phase also involve HLH-mediated interactions affecting regulators of the G1/S transition. We have found that Id2 augments apoptosis in both interleukin-3 (IL-3)-dependent 32D.3 myeloid progenitors and U2OS osteosarcoma cells. We could not detect a similar activity for Id3. In contrast to the effects of Id2 on differentiation and cell proliferation, Id2-mediated apoptosis is independent of HLH-mediated dimerization. The ability of Id2 to promote cell death resides in its N-terminal region and is associated with the enhanced expression of a known component of the programmed cell death pathway, the proapoptotic gene BAX.

scholarly journals Contribution of Inhibitor of Differentiation and Estrogenic Endocrine Disruptors to Neurocognitive Disorders

2018 ◽  
Vol 6 (3) ◽  
pp. 61 ◽  
Author(s):  
Andrea Avecilla ◽  
Mayur Doke ◽  
Jeremy Jovellanos ◽  
Vincent Avecilla
Keyword(s):  
Public Health ◽  
Endocrine Disruptors ◽  
Essential Role ◽  
Environmental Pollutants ◽  
Public Health Problem ◽  
Neurocognitive Disorders ◽  
Helix Loop Helix ◽  
Id Proteins ◽  
Hlh Transcription Factors ◽  
The Impact

The devastating growth in the worldwide frequency of neurocognitive disorders and its allied difficulties, such as decline in memory, spatial competency, and ability to focus, poses a significant psychological public health problem. Inhibitor of differentiation (ID) proteins are members of a family of helix-loop-helix (HLH) transcription factors. ID proteins have been demonstrated to be involved in neurodevelopmental and depressive diseases and, thus, may influence neurocognitive deficiencies due to environmental exposure. Previously, it has been demonstrated that environmental factors, such as estrogenic endocrine disruptors (EEDs), have played an essential role in the influence of various neurocognitive disorders such as Alzheimer’s, dementia, and Parkinson’s disease. Based on this increasing number of reports, we consider the impact of these environmental pollutants on ID proteins. Better understanding of how these ID proteins by which EED exposure can affect neurocognitive disorders in populations will prospectively deliver valuable information in the impediment and regulation of these diseases linked with environmental factor exposure.

scholarly journals Contribution of Inhibitor of Differentiation (ID) and Estrogenic Endocrine Disruptors to Neurocognitive Disorders

2018 ◽  
Author(s):  
Andrea Avecilla ◽  
Mayur Doke ◽  
Jeremy Jovellanos ◽  
Vincent Avecilla
Keyword(s):  
Public Health ◽  
Endocrine Disruptors ◽  
Essential Role ◽  
Environmental Pollutants ◽  
Public Health Problem ◽  
Neurocognitive Disorders ◽  
Helix Loop Helix ◽  
Id Proteins ◽  
Hlh Transcription Factors ◽  
The Impact

The devastating growth in the worldwide frequency of neurocognitive disorders and its allied difficulties such as decline in memory, spatial competency, and ability to focus poses a significant psychological public health problem. Inhibitor of Differentiation (ID) proteins are members of a family of helix-loop-helix (HLH) transcription factors. ID proteins have been demonstrated to be involved in neurodevelopmental & depressive diseases and thus may influence neurocognitive deficiencies due to environmental exposure. Previously, it has been demonstrated that environmental factors such as estrogenic endocrine disruptors (EEDs) have played an essential role in the influence of various neurocognitive disorders such as Alzheimer’s, Dementia, and Parkinson’s disease. Based on this increasing number of reports, we consider the impact of these environmental pollutants on ID proteins. Better understanding of how these ID proteins by which EED exposure can affect neurocognitive disorders in populations will prospectively deliver valuable information in the impediment and regulation of these diseases linked with environmental factor exposure.

scholarly journals Modulation of Basic Helix-Loop-Helix Transcription Complex Formation by Id Proteins during Neuronal Differentiation

2001 ◽  
Vol 277 (11) ◽  
pp. 9118-9126 ◽  
Author(s):  
Annika Jögi ◽  
Paula Persson ◽  
Anna Grynfeld ◽  
Sven Påhlman ◽  
Håkan Axelson
Keyword(s):  
Complex Formation ◽  
Neuronal Differentiation ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Id Proteins

scholarly journals Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2

2018 ◽  
Vol 115 (32) ◽  
pp. 8155-8160 ◽  
Author(s):  
Sourav Banerjee ◽  
Chenggong Ji ◽  
Joshua E. Mayfield ◽  
Apollina Goel ◽  
Junyu Xiao ◽  
...  
Keyword(s):  
Curcuma Longa ◽  
Xenograft Model ◽  
Proteasome Inhibition ◽  
Binding Pocket ◽  
Tumor Burden ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Dual Specificity ◽  
Immunocompromised Mice

Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.

scholarly journals Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wen-Xi Tan ◽  
Ge Sun ◽  
Meng-Yuan Shangguan ◽  
Zhi Gui ◽  
Yang Bao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cisplatin Resistance ◽  
Gynecological Cancer ◽  
Acquired Resistance ◽  
Tumor Burden ◽  
Human Patient ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.

scholarly journals Insect antimicrobial peptides show potentiating functional interactions against Gram-negative bacteria

2015 ◽  
Vol 282 (1806) ◽  
pp. 20150293 ◽  
Author(s):  
Mohammad Rahnamaeian ◽  
Małgorzata Cytryńska ◽  
Agnieszka Zdybicka-Barabas ◽  
Kristin Dobslaff ◽  
Jochen Wiesner ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Acquired Resistance ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Gram Negative ◽  
Functional Interactions ◽  
Trade Offs ◽  
Low Concentrations ◽  
Chaperone Network ◽  
Cell Growth And Viability

Antimicrobial peptides (AMPs) and proteins are important components of innate immunity against pathogens in insects. The production of AMPs is costly owing to resource-based trade-offs, and strategies maximizing the efficacy of AMPs at low concentrations are therefore likely to be advantageous. Here, we show the potentiating functional interaction of co-occurring insect AMPs (the bumblebee linear peptides hymenoptaecin and abaecin) resulting in more potent antimicrobial effects at low concentrations. Abaecin displayed no detectable activity against Escherichia coli when tested alone at concentrations of up to 200 μM, whereas hymenoptaecin affected bacterial cell growth and viability but only at concentrations greater than 2 μM. In combination, as little as 1.25 μM abaecin enhanced the bactericidal effects of hymenoptaecin. To understand these potentiating functional interactions, we investigated their mechanisms of action using atomic force microscopy and fluorescence resonance energy transfer-based quenching assays. Abaecin was found to reduce the minimal inhibitory concentration of hymenoptaecin and to interact with the bacterial chaperone DnaK (an evolutionarily conserved central organizer of the bacterial chaperone network) when the membrane was compromised by hymenoptaecin. These naturally occurring potentiating interactions suggest that combinations of AMPs could be used therapeutically against Gram-negative bacterial pathogens that have acquired resistance to common antibiotics.

Effect on response to neoadjuvant chemotherapy in high-grade serous ovarian cancer by inhibiting the GAS6/AXL pathway and inducing homologous recombination deficiency.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6080-6080
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Michael Driscoll Toboni ◽  
Hollie M Noia ◽  
Danny Wilke ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Neoadjuvant Chemotherapy ◽  
Mouse Models ◽  
Poor Response ◽  
Tumor Burden ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Response To Neoadjuvant Chemotherapy

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.

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