scholarly journals S18-phosphorylation of USP7 regulates interaction with TCEAL4 that defines specific complexes and potentially distinct functions.

2021 ◽  
Author(s):  
Francesca Querques ◽  
Sarah Darling ◽  
Izaak Cheetham-Wilkinson ◽  
Robbert Kim ◽  
Dharani Kosala Hapangama ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Protein Interactions ◽  
Cancer Cell Lines ◽  
Pleiotropic Effects ◽  
Cellular Activity ◽  
Selective Inhibitors ◽  
Multiple Cancer ◽  
Lower Abundance

USP7 is a nuclear deubiquitylase (DUB) with multiple cancer-associated substrates for which selective inhibitors are available, yet it remains unclear how the pleiotropic effects of USP7 are regulated. We report that S18-phosphorylation does not influence USP7 catalytic activity but instead confers selectivity for protein interactions. In particular, non-S18-phosphorylatable USP7 preferentially interacts with USP11 and TRIM27, together with TCEAL1 and TCEAL4 whose functions are unknown. Intriguingly, USP7 can interact with two cellular forms of TCEAL4, but USP11 only interacts with a lower abundance K142 mono-ubiquitylated form (TCEAL4-Ub), which can scaffold a complex containing both DUBs. Whilst USP11 and TCEAL4 are both USP7 substrates, TCEAL4-Ub levels are specifically maintained by USP11 with their levels positively correlated in cancer cell lines. Together these data illustrate how USP7 phosphorylation and TCEAL4 ubiquitylation combine to define distinct USP7 complexes. As TCEAL4 itself interacts with proteins involved in ubiquitylation and various forms of DNA regulation, these complexes may direct cellular activity of USP7.

Abstract 1390: Inhibition of the catalytic activity of hUNG2 sensitizes multiple cancer cell lines to 5-FdUrd killing

2020 ◽  
Author(s):  
Eric S. Christenson ◽  
Junru Cui ◽  
Anthony Gizzi ◽  
Mesfin Meshesha ◽  
James T. Stivers
Keyword(s):  
Catalytic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Multiple Cancer

scholarly journals A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition

2008 ◽  
Vol 415 (1) ◽  
pp. 97-110 ◽  
Author(s):  
Neil E. Torbett ◽  
Antonio Luna-Moran ◽  
Zachary A. Knight ◽  
Andrew Houk ◽  
Mark Moasser ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Therapeutics ◽  
Cancer Cell Lines ◽  
Genetic Alterations ◽  
Breast Cancer Cell Lines ◽  
Selective Inhibitors

The PI3K (phosphoinositide 3-kinase) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small-molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we have demonstrated that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110α inhibitors were generally effective in inhibiting the phosphorylation of PKB (protein kinase B)/Akt and S6, two downstream components of PI3K signalling, in most cell lines examined. In contrast, p110β-selective inhibitors only reduced PKB/Akt phosphorylation in PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing cell-cycle arrest in the G1 phase, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell-cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signalling pathways. Taken together, our data indicate that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts.

scholarly journals Species D Adenoviruses as Oncolytic Viral Vectors

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1399
Author(s):  
Brianna L. Bullard ◽  
Brigette N. Corder ◽  
Eric A. Weaver
Keyword(s):  
Blood Coagulation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Neutralizing Antibodies ◽  
Coagulation Factor ◽  
Cancer Cell Lines ◽  
Factor X ◽  
Multiple Cancer ◽  
Iodide Uptake ◽  
Oncolytic Adenoviruses

Oncolytic adenoviruses (Ad) have shown promising results in the therapeutic treatment of cancer. Ad type 5 (Ad5) is the most extensively utilized Ad type. However, several limitations exist to using Ad5 as an oncolytic virus, including high levels of anti-Ad5 neutralizing antibodies in the population, binding of the Ad5 hexon to blood coagulation factor X leading to liver sequestration and toxicity, and reduced expression of the primary receptor CAR on many tumors. Here, we use in vitro methods to explore the oncolytic potential of four alternative Ad types (Ad26, 28, 45, and 48) belonging to the species D Ad subgroup and developed replication-competent species D Ads expressing the human sodium iodide symporter protein (hNIS) for combination radiovirotherapy. We evaluated the species D Ad vectors transduction, replication, cytotoxicity, and gene expression in six different cancer cell lines. Species D Ads showed the greatest transduction and cytotoxic killing in the SKBR3 breast cancer cells, followed by 293, A549, and HepG2 cells, however the cytotoxicity was less than the wild type Ad5 virus. In contrast, species D Ads showed limited transduction and cytotoxicity in the Hela and SKOV3 cancer cell lines. These species D Ad vectors also successfully expressed the hNIS gene during infection leading to increased iodide uptake in multiple cancer cell lines. These results, the low seroprevalence of anti-species D antibodies, and the lack of binding to blood coagulation FX, support further exploration of species D Ads as alternative oncolytic adenoviruses against multiple types of cancer.

Anti-EpCAM XmAb antibodies with improved cytotoxicity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12506-12506 ◽  
Author(s):  
O. Vafa ◽  
S. Kharki ◽  
J. Vielmetter ◽  
A. Chamberlain ◽  
P. Hammond ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Clinical Efficacy ◽  
Cancer Cell Lines ◽  
In Vitro Cytotoxicity ◽  
Binding Assays ◽  
Multiple Cancer ◽  
Effector Cells ◽  
Dependent Cell

12506 Background: The epithelial cell adhesion molecule (EpCAM), also known as epithelial protein 2 (EGP-2) or 17–1A antigen, is a trans-membrane protein expressed on the surfaces of most carcinomas, including those of pancreatic, colorectal, prostate, breast, kidney, lung, and ovarian origins. Moderate affinity antibodies (Abs) such as 17–1A (Kd ∼ 10−7 nM) have been safe in humans albeit with limited clinical efficacy. Attempts to improve clinical efficacy by enhancing antigen affinity (Kd ∼ 10−9 nM) have led to serious clinical toxicity, including pancreatitis. These observations raise the question of whether a moderate affinity Ab with enhanced effector function will be both safe and clinically efficacious. Methods: We applied our proprietary XmAb™ technologies to humanize the 17–1A variable domain and engineer a human IgG1 Fc domain to increase affinity for the activating receptor FcγRIIIa. Ab binding to Ep-CAM or to Fc receptors was tested with Biacore and/or AlphaScreen binding assays. In vitro cytotoxic activity against representative cancer cell lines was measured with Antibody Dependent Cell-mediated Cytotoxicity (ADCC) assays, using human PBMC as effector cells. Results: Humanized anti-EpCAM Abs have affinity for EpCAM similar to the parent 17–1A. Affinity for the activating FcγRIIIa was increased 100-fold relative to a control Ab with an IgG1 Fc domain. As expected, these Abs exhibit dramatically enhanced ADCC against multiple cancer cell lines relative to 17–1A and IgG1 control Abs. Despite their moderate affinity for EpCAM, these novel Abs have in vitro cytotoxicity comparable to the high affinity Ab ING-1. CDC activities of these Abs were similar to chimeric 17–1A. Conclusions: We have demonstrated that antibodies with moderate affinity for EpCAM and increased FcγRIIIa affinity exhibit superior cancer cell killing via an ADCC mechanism. The humanized nature and the increased cytotoxicity of anti-EpCAM XmAb™ antibodies make them promising candidates for clinical development of a novel pan-carcinoma Ab that is superior to 17–1A. [Table: see text]

scholarly journals Design, Synthesis and Anticancer Profile of New 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect

2021 ◽  
Vol 22 (19) ◽  
pp. 10491
Author(s):  
Mohammed S. Abdel-Maksoud ◽  
Ahmed A. B. Mohamed ◽  
Rasha M. Hassan ◽  
Mohamed A. Abdelgawad ◽  
Garri Chilingaryan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Pyrimidine Ring ◽  
Cancer Cell Lines ◽  
Inhibitory Effect ◽  
Docking Studies ◽  
Binding Modes ◽  
Multiple Cancer

A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a–n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 µM) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 µM. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.

Diacylglycerol kinase α‐selective inhibitors induce apoptosis and reduce viability of melanoma and several other cancer cell lines

2018 ◽  
Vol 120 (6) ◽  
pp. 10043-10056 ◽  
Author(s):  
Atsumi Yamaki ◽  
Rino Akiyama ◽  
Chiaki Murakami ◽  
Saki Takao ◽  
Yuki Murakami ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Diacylglycerol Kinase ◽  
Cancer Cell Lines ◽  
Selective Inhibitors

scholarly journals HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

2015 ◽  
Vol 13 (7) ◽  
pp. 356-376 ◽  
Author(s):  
Paul A. Johnston ◽  
Malabika Sen ◽  
Yun Hua ◽  
Daniel P. Camarco ◽  
Tong Ying Shun ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cell Lines ◽  
Cancer Cell ◽  
Neck Cancer ◽  
Cancer Cell Lines ◽  
Selective Inhibitors ◽  
Stat3 Pathway ◽  
Pathway Activation

scholarly journals ATP modulates PTEN subcellular localization in multiple cancer cell lines

2008 ◽  
Vol 17 (18) ◽  
pp. 2877-2885 ◽  
Author(s):  
Glenn P. Lobo ◽  
Kristin A. Waite ◽  
Sarah M. Planchon ◽  
Todd Romigh ◽  
Janet A. Houghton ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Multiple Cancer

scholarly journals TBIO-26. NON-CANONICAL OPEN READING FRAMES ENCODE FUNCTIONAL PROTEINS ESSENTIAL FOR CANCER CELL SURVIVAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii471-iii471
Author(s):  
John Prensner ◽  
Oana Enache ◽  
Victor Luria ◽  
Karsten Krug ◽  
Karl Clauser ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Protein Translation ◽  
Cancer Cell Lines ◽  
Open Reading Frames ◽  
Sequencing Analysis ◽  
Multiple Cancer ◽  
Cancer Types ◽  
Non Coding Rnas ◽  
Reading Frames

Abstract The brain is the foremost non-gonadal tissue for expression of non-coding RNAs of unclear function. Yet, whether such transcripts are truly non-coding or rather the source of non-canonical protein translation is unknown. Here, we used functional genomic screens to establish the cellular bioactivity of non-canonical proteins located in putative non-coding RNAs or untranslated regions of protein-coding genes. We experimentally interrogated 553 open reading frames (ORFs) identified by ribosome profiling for three major phenotypes: 257 (46%) demonstrated protein translation when ectopically expressed in HEK293T cells, 401 (73%) induced gene expression changes following ectopic expression across 4 cancer cell types, and 57 (10%) induced a viability defect when the endogenous ORF was knocked out using CRISPR/Cas9 in 8 human cancer cell lines. CRISPR tiling and start codon mutagenesis indicated that the biological impact of these non-canonical ORFs required their translation as opposed to RNA-mediated effects. We functionally characterized one of these ORFs, G029442—renamed GREP1 (Glycine-Rich Extracellular Protein-1)—as a cancer-implicated gene with high expression in multiple cancer types, such as gliomas. GREP1 knockout in >200 cancer cell lines reduced cell viability in multiple cancer types, including glioblastoma, in a cell-autonomous manner and produced cell cycle arrest via single-cell RNA sequencing. Analysis of the secretome of GREP1-expressing cells showed increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth inhibitory effect of GREP1 knock-out. Taken together, these experiments suggest that the non-canonical ORFeome is surprisingly rich in biologically active proteins and potential cancer therapeutic targets deserving of further study.

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