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The interaction of CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly

ABSTRACT: The interaction of CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly

PROVIDER: PRJNA1298828 | ENA |

REPOSITORIES: ENA

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The interaction of CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly

Project description:The widespread clinical application of paclitaxel (PTX) in cancer treatment has been significantly limited by the emergence of drug resistance and drug-tolerant persisters. Through genome-wide CRISPR/Cas9 screening, we identified cell division cycle 6 (CDC6) as a critical determinant of cell adhesion-mediated paclitaxel resistance. CDC6, an essential DNA replication licensing factor, functions through a pathway distinct from well-characterized resistance mechanisms. The depletion of CDC6 considerably increases paclitaxel-induced cell death. Beyond its established role in stabilizing chromosomes, our findings indicate that tropomodulin-3 (Tmod3) interacts with CDC6 in the cytoplasm. This interaction enhances CDC6 protein stability and drives drug-resistant phenotypes through regulating actin cytoskeleton remodeling and facilitating focal adhesion assembly. In addition, pharmacological or genetic inhibition of CDC6 notably sensitizes the antitumor efficacy of paclitaxel both in vitro and in vivo. Collectively, our studies elucidate the mechanisms through which CDC6 functions as a key regulator of paclitaxel resistance and provide a potential strategy to enhance paclitaxel efficacy through cytoskeletal-adhesion axis modulation.

2025-08-31 | GSE304051 | GEO

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

Project description:Aberrant tyrosine kinase activity can influence tumor growth and is regulated by phosphorylation. Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. We investigated phosphorylated kinases as target in PDAC. Mass spectrometry-based phosphoproteomic analysis was performed of PDAC cell lines to evaluate active kinases. Pathway analysis and inferred kinase activity was performed to identify novel targets. We investigated targeting of focal adhesion kinase in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Phosphoproteome analysis upon treatment was performed to evaluate signaling..PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases. Non-receptor kinase, focal adhesion kinase (FAK), was identified in all cell lines by our phosphoproteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. In conclusion, our study shows a high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel

2021-09-10 | PXD024548 | Pride

Focal Adhesion Kinase Dependent Expression

Project description:The goal of this study was to identify transcripts, which are differentially regulatulated in the presence and absence of Focal Adhesion Kinase. As Focal Adhesion Kinase activity can depend upon cell density (Snijder et al. Nature 2009), biological replicates where cells, were seeded very sparsely or confluently, were used. Focal Adhesion Kinase Knockout (ATCC CRL-2644) and Rescue Cells (Sieg et al. 1998, clone DA2) were seeded at two different concentrations. Replicas refer to biological replicates, performed on different days. Only one single technical replicate has been done per biological replicate.

2013-09-17 | E-GEOD-43873 | biostudies-arrayexpress

Focal Adhesion Kinase Dependent Expression

2013-09-17 | GSE43873 | GEO

Podocyte Focal Adhesion Proteome

Project description:Expression proteomics analysis of focal adhesion complexes isolated from a human immortalized podocyte cell line.

2018-12-14 | PXD010626 | Pride

YAP regulates cell mechanics by controlling focal adhesion assembly

Project description:YAP regulates cell mechanics by controlling focal adhesion assembly

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Remodeling of the focal adhesion complex by hydrogen-peroxide- induced senescence

Project description:Cellular senescence is a phenotype characterized by cessation of cell division, which can be caused by exhaustive replication or environmental stress. It is involved in age-related pathophysiological conditions and affects both the cellular cytoskeleton and the prime cellular mechanosensors, focal adhesion complexes. While the size of focal adhesions increases during senescence, it is unknown if and how this is accompanied by a remodeling of the internal focal adhesion structure. Our study uses metal-induced energy transfer to study the axial dimension of focal adhesion proteins from oxidative-stress-induced senescent cells with nanometer precision, and compares these to unstressed cells. We influenced cytoskeletal tension and the functioning of mechanosensitive ion channels using drugs and studied the combined effect of senescence and drug intervention on the focal adhesion structure. We find that H 2 O 2 induced restructuring of the focal adhesion complex indicates a loss of tension and altered talin complexation. Mass spectroscopy-based proteomics confirmed the differential regulation of several cytoskeletal proteins induced by H 2 O 2 treatment.

2023-07-06 | PXD041766 | Pride

Canonical Wnt Induces Focal Adhesion and Integrin Beta-1 Endocytosis

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AKT1E17K activates focal adhesion kinase and promotes melanoma brain metastasis

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MITF reprograms the extracellular matrix and focal adhesion in melanoma

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