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Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer
Conclusions We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.
Source: Gut - July 7, 2016 Category: Gastroenterology Authors: Kloth, M., Ruesseler, V., Engel, C., Koenig, K., Peifer, M., Mariotti, E., Kuenstlinger, H., Florin, A., Rommerscheidt-Fuss, U., Koitzsch, U., Wodtke, C., Ueckeroth, F., Holzapfel, S., Aretz, S., Propping, P., Loeffler, M., Merkelbach-Bruse, S., Odenthal, Tags: Colon cancer Source Type: research

Abstract 5097: APE1/Ref-1 promotes cell adhesion and migration in cervical cancer cells
In this study, we are the first to report that APE1/Ref-1 activates cell adhesion-related proteins to trigger cell migration. To investigate whether APE1/Ref-1 is involved in cell adhesion in normal fibroblasts, an adhesion assay was performed using GM00637 human fibroblast cell lines stably overexpressing APE1/Ref-1. Cell adhesion to vitronectin, a known ligand of the adhesion molecules integrin ανβ3 and integrin ανβ5, was significantly increased in APE1/Ref-1-overexpressing GM00637 cells compared to control fibroblast cells. FACS analysis showed APE1/Ref-1 induces the expression and activation of adhesion molecules...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Kim, M., You, H. J., Kim, D. J. Tags: Tumor Biology Source Type: research

BAD-mediated apoptotic pathway is associated with human cancer development.
Abstract The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive ...
Source: International Journal of Molecular Medicine - February 5, 2015 Category: Molecular Biology Authors: Stickles XB, Marchion DC, Bicaku E, Al Sawah E, Abbasi F, Xiong Y, Bou Zgheib N, Boac BM, Orr BC, Judson PL, Berry A, Hakam A, Wenham RM, Apte SM, Berglund AE, Lancaster JM Tags: Int J Mol Med Source Type: research

Abstract 5362: Deficiencies in mismatch repair proteins induce elevated levels of acrolein-derived 1,N2-propanodeoxyguanosine and apoptosis in human colon cancer cells treated with acrolein
This study shows that MMR proteins, MLH1 and MSH2, are involved in the repair of Acr-dG. The results also suggest that Acr-dG may cause double-strand breaks which lead to apoptosis. Whether MMR acts as an independent repair pathway for Acr-dG or MMR proteins cross-talk and interact with other DNA repair pathways, such as NER, is under investigation. (Supported by NCI grant CA43159) Citation Format: Jishen Pan, Zhuoli Xuan, Marcin Dyba, Yongwei Zhang, Ying Fu, Rabindra Roy, Louis M. Weiner, Fung-Lung Chung. Deficiencies in mismatch repair proteins induce elevated levels of acrolein-derived 1,N2-propanodeoxyguanosine and apo...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Pan, J., Xuan, Z., Dyba, M., Zhang, Y., Fu, Y., Roy, R., Weiner, L. M., Chung, F.-L. Tags: Carcinogenesis Source Type: research

Abstract 493: NRF2 modulates sensitivity to thymidylate synthase inhibitors in colon cancer cells
Thymidylate synthase (TYMS) catalyzes the reductive methylation of dUMP, and is the sole de novo source of thymidine for DNA replication and repair. As such, it is an important target of chemotherapeutic drugs, particularly the fluoropyrimidines 5-fluorouracil (FUra) and 5-fluoro-2’-deoxyuridine (FdUrd), as well as the folate analog raltitrexed (RTX). In cells, these drugs are metabolized to derivatives that bind to and inhibit TYMS, leading to depletion of thymidine levels, dysregulation of redox metabolism, generation of oxidative stress, and, eventually, apoptotic cell death. Gene expression profiles of FUra-treated H...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Clinton, S. A., Barbour, K. W., Ozer, U., Berger, F. G. Tags: Molecular and Cellular Biology Source Type: research

Reduced migration of MLH1 deficient colon cancer cells depends on SPTAN1
Conclusions: These data suggest that SPTAN1 levels decreased in concordance with MLH1 reduction and impaired cellular mobility in MLH1 deficient colon cancer cells. Therefore, aggressiveness of MLH1-positive CRC might be related to SPTAN1.
Source: Molecular Cancer - January 24, 2014 Category: Cancer & Oncology Authors: Inga HinrichsenBenjamin ErnstFranziska NuberSandra PassmannDieter SchäferVerena SteinkeNicolaus FriedrichsGuido PlotzStefan ZeuzemAngela Brieger Source Type: research

{beta}1Pix Interacts Directly with {beta}-Catenin Cell Biology
We report the novel observations that β1Pix binds directly to β-catenin, an action requiring both the β1Pix DH and dimerization domains but not β1Pix GEF activity. In human colon cancer cells, activation of β-catenin signaling with LiCl decreased β1Pix/β-catenin association in the cytosol and increased nuclear binding of β-catenin to β1Pix. Nuclear association of β1Pix and β-catenin was independent of Rac1 expression and activation; down- and up-regulating Rac1 expression levels did not alter nuclear β1Pix/β-catenin association. Ectopic β1Pix expression enhanced LiCl-induced β-catenin transcriptional activit...
Source: Journal of Biological Chemistry - November 22, 2013 Category: Chemistry Authors: Chahdi, A., Raufman, J.-P. Tags: Signal Transduction Source Type: research

MLN4924 Genome-Wide RNAi Screen
MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic...
Source: Cancer Research - January 2, 2013 Category: Cancer & Oncology Authors: Blank, J. L., Liu, X. J., Cosmopoulos, K., Bouck, D. C., Garcia, K., Bernard, H., Tayber, O., Hather, G., Liu, R., Narayanan, U., Milhollen, M. A., Lightcap, E. S. Tags: Molecular and Cellular Pathobiology Source Type: research

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