scholarly journals Coessentiality and cofunctionality: a network approach to learning genetic vulnerabilities from cancer cell line fitness screens

2017 ◽  
Author(s):  
Traver Hart ◽  
Clara Koh ◽  
Jason Moffat
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Genetic Interaction ◽  
Synthetic Lethality ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Ovarian Cancer Cells ◽  
Specific Gene ◽  
Network Clustering

AbstractGenetic interaction networks are a powerful approach for functional genomics, and the synthetic lethal interactions that comprise these networks offer a compelling strategy for identifying candidate cancer targets. As the number of published shRNA and CRISPR perturbation screens in cancer cell lines expands, there is an opportunity for integrative analysis that goes further than pairwise synthetic lethality and discovers genetic vulnerabilities of related sets of cell lines. We re-analyze over 100 high-quality, genome-scale shRNA screens in human cancer cell lines and derive a quantitative fitness score for each gene that accurately reflects genotype-specific gene essentiality. We identify pairs of genes with correlated essentiality profiles and merge them into a cancer coessentiality network, where shared patterns of genetic vulnerability in cell lines give rise to clusters of functionally related genes in the network. Network clustering discriminates among all three defined subtypes of breast cancer cell lines (basal, luminal, and Her2-amplified), and further identifies novel subsets of Her2+ and ovarian cancer cells. We demonstrate the utility of the network as a platform for both hypothesis-driven and data-driven discovery of context-specific essential genes and their associated biomarkers.

scholarly journals Synthesis, Characterization and Biological Evaluation of Metal Adamantyl 2-Pyridylhydrazone Complexes

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2530
Author(s):  
Ihsan A. Shehadi ◽  
Fatima-Azzahra Delmani ◽  
Areej M. Jaber ◽  
Hana Hammad ◽  
Murad A. AlDamen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Direct Methods ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Colorectal Cancer Cell Line ◽  
Breast Cancer Cell Lines ◽  
Human Cancer Cell Lines

Four new complexes derived from adamantly containing hydrazone (APH) ligand with Cu(II) (1), Co(II) (2), Ni(II) (3) and Zn(II) (4), have been synthesized and characterized using different physicochemical methods. The structure of the ligand APH and its copper complex 1 have been established by single-crystal X-ray diffraction direct methods, which reveal that complex 1 has distorted square-pyramidal geometry. Complexes 1–4 are screened against seven human cancer cell lines namely, breast cancer cell lines (MCF7, T47D, MDA-MB-231), prostate cancer cell lines (PC3, DU145) and the colorectal cancer cell line Coco-2, for their antiproliferative activities. Complex 1 has shown a promising anticancer activity compared to the other ones. The structural and spectroscopic analysis of APH and its complexes are confirmed by DFT calculations.

High-Throughput RNA Interference Screening Identifies Synthetic Lethality Between Oncogenic KRAS Dependency and Suppression of STK33

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3806-3806
Author(s):  
Claudia Scholl ◽  
Stefan Frohling ◽  
Ian F. Dunn ◽  
David A. Barbie ◽  
Anna C. Schinzel ◽  
...  
Keyword(s):  
Rna Interference ◽  
Protein Kinase ◽  
Cell Viability ◽  
Cell Lines ◽  
Cancer Cell ◽  
High Throughput ◽  
Synthetic Lethality ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Dependent Manner

Abstract Activating RAS mutations are among the most common pathogenetic events in a broad spectrum of hematologic malignancies and epithelial tumors. However, oncogenic RAS has thus far not proven to be a tractable target for therapeutic intervention. An alternative to direct targeting of known oncogenes is to perform “synthetic lethality” screens to identify genes that are selectively required for cell viability in the context of specific cancer-causing mutations. Using this approach, we have discovered a synthetic lethal interaction between mutant KRAS, the most frequently mutated oncogene in human cancer, and inactivation of the gene encoding the STK33 serine/threonine protein kinase. To identify genes that are essential for cell viability in the context of mutant KRAS, we performed high-throughput loss-of-function RNA interference (RNAi) screens in eight human cancer cell lines (mutant KRAS, n=4; wildtype KRAS, n=4), representing seven different tumor types (acute myeloid leukemia, multiple myeloma, colon cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma), as well as normal human fibroblasts and mammary epithelial cells. We screened each cell line with a subset of the short hairpin RNA (shRNA) library developed by the RNAi Consortium (http://www.broad.mit.edu/genome_bio/trc/rnai.html) that consists of 5,024 individual shRNA constructs targeting 1,011 human genes, including the majority of known and putative protein kinase and phosphatase genes and a selection of known cancer-related genes. In these cell lines, suppression of STK33 preferentially inhibited the viability and proliferation of cells that were dependent on mutant KRAS. The differential requirement for STK33 based on oncogenic KRAS dependency was confirmed in 16 additional cell lines using in vitro transformation assays and human tumor xenograft models. Biochemical analyses support the hypothesis that STK33 promotes cell growth and survival in a kinase activity-dependent manner by regulating the activity of S6K1 as well as BAD-induced apoptosis selectively in mutant KRAS-dependent cells. Notably, molecular genetic characterization of cancer cell lines and analysis of patient-derived genomic data sets indicate that STK33 is not frequently mutated or overexpressed in human tumors. These observations identify STK33 as a potential target for the treatment of mutant KRAS-driven cancers that may have a broad therapeutic index in normal versus malignant cells, and illustrate the potential of RNAi for discovering critical functional dependencies created by oncogenic mutations that cannot be identified using other genomic technologies.

scholarly journals Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold(III) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 871
Author(s):  
Giulia Gorini ◽  
Francesca Magherini ◽  
Tania Fiaschi ◽  
Lara Massai ◽  
Matteo Becatti ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Thioredoxin Reductase ◽  
Cancer Cell Lines ◽  
Ovarian Cancer Cells ◽  
Subsequent Formation ◽  
Apoptotic Signaling

Au2phen ((2,9-dimethyl-1,10-phenanthroline)2Au2(µ-O)2)(PF6)2 and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)2Au2(µ-O)2)(PF6)2 are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase.

scholarly journals Anticancer Activity of Ag(I) N-Heterocyclic Carbene Complexes Derived from 4,5-Dichloro-1H-Imidazole

2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Doug A. Medvetz ◽  
Khadijah M. Hindi ◽  
Matthew J. Panzner ◽  
Andrew J. Ditto ◽  
Yang H. Yun ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Silver Complexes ◽  
Carbene Complexes ◽  
Human Cancer Cell Lines

A class of Ag(I) N-heterocyclic carbene silver complexes, 1–3, derived from 4,5-dichloro-1H-imidazole has been evaluated for their anticancer activity against the human cancer cell lines OVCAR-3 (ovarian), MB157 (breast), and Hela (cervical). Silver complexes 1–3 are active against the ovarian and breast cancer cell lines. A preliminary in vivo study shows 1 to be active against ovarian cancer in mice. The results obtained in these studies warrant further investigation of these compounds in vivo.

scholarly journals Chemical Analysis of the Edible Mushroom Tricholoma populinum: Steroids and Sulfinyladenosine Compounds

2017 ◽  
Vol 12 (10) ◽  
pp. 1934578X1701201 ◽  
Author(s):  
Bernadett Kovács ◽  
Zoltán Béni ◽  
Miklós Dékány ◽  
Orsolya Orbán-Gyapai ◽  
Izabella Sinka ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Edible Mushroom ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Human Cancer Cell Lines ◽  
Chemical Structures ◽  
Diphenyltetrazolium Bromide

Ten compounds have been identified in the methanol extract of cottonwood mushroom ( Tricholoma populinum J.E. Lange), 9 of them for the first time in this species. Besides adenosine (8) and nicotinamide (7) the isolated compounds were ergostane type steroids (1-6) and rare sulfinyladenosine constituents (9 and 10). The chemical structures of these compounds were elucidated by means of extensive spectroscopic methods (NMR and MS). Compounds 3-6 were evaluated for their potential antiproliferative activity against human cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The xanthine oxidase (XO) inhibitory activity of 7-10 has been examined by spectrophotometric method. Cerevisterol (3), its methylated derivative (5) and 3-glycoside of ergosterol peroxide (6) showed significant antiproliferative activity on human breast cancer cell lines.

TSGA10 Expression Status in Breast Cancer: The Role of Microenvironmental Changes

2020 ◽  
Author(s):  
Marzieh Marzbany ◽  
Amir Hossein Norooznezhad ◽  
Zohreh Hoseinkhani ◽  
Azadeh Mahnam ◽  
Kiumaras Eslampia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Specific Gene ◽  
Mcf 7

Abstract Background: Testis-specific gene antigen (TSGA10) mainly involves in spermatogenesis and embryogenesis. In the new defined roles, being a tumor suppressor agent or a cancer/testis antigen (CTA) is still unclear for this protein. The current study aimed to examine exact role of TSGA10 as a tumor suppressor or CTA in breast cancer and evaluate the role of microenvironment on its expression. Methods: This study evaluated the expression of TSGA10 and hypoxia-inducible factor 1α (HIF-1α) in two different breast cancer cell lines (MCF-7 and MDA-MB23) as well as their control (MCF10A) using real-time PCR. Moreover, expression of the mentioned genes evaluated in samples obtained from tumoral tissues with two types of controls: paired (tumor-free margin) and unpaired (healthy individuals). Also, in order to asses TSGA10 levels in the tumoral tissues, western blotting was performed. Furthermore, to evaluate the role epigenetic changes on TSGA10 expression, breast cancer cell lines were treated with a histone deacetylase inhibitor (HDACI) as well as H2O2 for oxidative stress induction. Results: The current study evaluated 36 patients diagnosed with breast cancer as well as 10 healthy controls. According to the results, it was shown that 35 (97.7%) and 1 (2.8%) of patients were diagnosed with ductal and lobular carcinomas respectively. The TSGA10 levels in the tumoral samples showed 1.38±0.014-fold decrease and 1.41±0.127-fold increase compared with their paired (P<0.001) and unpaired (P<0.001) controls respectively. Moreover, results of blotting in tumoral tissues expressed significant decrease in TSGA10 levels in comparison to the paired controls (P<0.01). Among the cell lines, TSGA10 expression in MCF-7 and MDA-MB23 cells had 4.9±0.283 and 4.21±0.163 folds of decrease in normoxic and 4.7±.0.283 and 7.1±0.141 folds of expression reduction in hypoxic condition respectively (all P<0.0001). Furthermore, the results showed that HIF-1α expression was up-regulated in both normoxic (P<0.01) and hypoxic (P<0.01) conditions. Also, TSGA10 expression increased up to 7.39±0.156 folds in MCF-7 cells after HDACI treatment (all P<0.01). However, MDA-MB23 cells firstly experienced a decrease and then a notable increase in TSGA10 expression (all P<0.01). Conclusion: Results of current study showed that TSGA10 seems to be tumor suppressor, however, further studies are necessary.

scholarly journals Highly Cancer Selective Antiproliferative Activity of Natural Prenylated Flavonoids

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2922 ◽  
Author(s):  
Agnieszka Bartmańska ◽  
Tomasz Tronina ◽  
Jarosław Popłoński ◽  
Magdalena Milczarek ◽  
Beata Filip-Psurska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Prenylated Flavonoids

Xanthohumol (XN) and four minor hops prenylflavonoids: α,β-dihydroxanthohumol (2HXN), isoxanthohumol (IXN), 8-prenylnaringenin (8PN), and 6-prenylnaringenin (6PN), were tested for antiproliferative activity towards human cancer and normal cell lines. Nonprenylated naringenin (NG) was used as a model compound. Xanthohumol, α,β-dihydroxanthohumol and 6-prenylnaringenin were the most active compounds. Xanthohumol exhibited higher antiproliferative activity than cisplatin (CP) against five cancer cell lines: ovarian resistant to cisplatin A2780cis, breast MDA-MB-231 and T-47D, prostate PC-3, and colon HT-29. Isoxanthohumol was more potent than cisplatin against breast cancer cell lines MDA-MB-231 and T-47D whereas 6-prenylnaringenin was stronger than cisplatin against breast cancer cell line T-47D. It was found that tested chalcones possessed highly selective antiproliferative activity towards all tested breast cancer lines compared to the normal breast MCF 10A cell line (the calculated selectivity index ranged from 5 to 10). Low antiproliferative activity of naringenin indicates the importance of the prenyl group with respect to antiproliferative activity.

Antiproliferative activity of ent-abietane lactones against resistant human cancer cell lines

Planta Medica ◽  
2008 ◽  
Vol 74 (09) ◽  
Author(s):  
N Duarte ◽  
H Lage ◽  
MJU Ferreira
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

The effects of phytoestrogen extracts isolated from elder flower on hormone production and proliferation of trophoblast tumour and breast cancer cell lines

2014 ◽  
Vol 74 (S 01) ◽  
Author(s):  
L Schröder ◽  
B Piechulla ◽  
M Chorbak ◽  
C Kuhn ◽  
S Schulze ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Hormone Production

Extracts from the marine fungus Neosartorya tsunodae and the soil fungus Neosartorya fischeri exhibit anti-proliferative and pro-apoptotic effects in human cancer cell lines

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
B Castro-Carvalho ◽  
A Ramos ◽  
M Prata-Sena ◽  
T Dethoup ◽  
S Buttachon ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Soil Fungus ◽  
Cancer Cell Lines ◽  
Marine Fungus ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Neosartorya Fischeri ◽  
Apoptotic Effects
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