Extracellular Matrix (ECM) and Cytoskeletal Modulation of Cellular Radiosensitivity

Stevenson, A. F. G.; Lange, Christopher S.

doi:10.3109/02841869709001322

Cited by 11 publications

(6 citation statements)

References 12 publications

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“…Confirmatory data for both issues are shown here as the tested A549 and H1299 human NSCLC cells show higher radioresistance as well as a diminished cytotoxic and radiosensitizing potential of cetuximab on adhesion to fibronectin. These findings corroborate published data in cells from other malignancies and on other drugs (41)(42)(43).…”

Section: Discussionsupporting

confidence: 83%

Cetuximab Attenuates Its Cytotoxic and Radiosensitizing Potential by Inducing Fibronectin Biosynthesis

et al. 2013

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Inherent and acquired resistance to targeted therapeutics continues to emerge as a major clinical obstacle. For example, resistance to EGF receptor targeting occurs commonly, more so than was expected, on the basis of preclinical work. Given emerging evidence that cancer cell-substrate interactions are important determinants of therapeutic sensitivity, we examined the impact of cell-fibronectin interactions on the efficacy of the EGF receptor antibody cetuximab, which is used widely for lung cancer treatment. Our results revealed the potential for cell-fibronectin interactions to induce radioresistance of human non-small cell lung cancer cells. Cell adhesion to fibronectin enhanced tumor cell radioresistance and attenuated the cytotoxic and radiosensitizing effects of cetuximab. Both in vitro and in vivo, we found that cetuximab treatment led to a remarkable induction of fibronectin biosynthesis. Mechanistic analyses revealed the induction was mediated by a p38-MAPK-ATF2 signaling pathway and that RNAi-mediated inhibition of fibronectin could elevate the cytotoxic and radiosensitizing potential of cetuximab. Taken together, our findings show how cell adhesion blunts cetuximab, which, by inducing fibronectin, generates a self-attenuating mechanism of drug resistance.

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Section: Discussionsupporting

confidence: 83%

Cetuximab Attenuates Its Cytotoxic and Radiosensitizing Potential by Inducing Fibronectin Biosynthesis

et al. 2013

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“…However, as shown by several groups (51)(52)(53)(54)(55), integrin-mediated cell-matrix interactions advantageously impact on normal and tumor cell survival after irradiation. This phenomenon is called cell adhesion-mediated radioresistance (9).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Hyperactive Integrin-Linked Kinase Leads to Increased Cellular Radiosensitivity

Cordes

2004

Cancer Research

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Integrin-linked kinase (ILK), bound to the cytoplasmic tails of integrin ␤1, ␤2, and ␤3, is thought to signal through AKT and glycogen synthase kinase-3␤ (GSK-3␤) for survival and proliferation regulation. To determine the role of ILK in the cellular radiation response, stably transfected A549 lung cancer cells overexpressing either wild-type (ILK-wk) or hyperactive ILK (ILK-hk) were studied for survival, signaling, proliferation, and examined in immunofluorescence and adhesion assays. Strong radiosensitization was observed in ILK-hk in contrast to ILK-wk mutants and empty vector controls. ILK small interfering RNA transfections showed radioresistance similar to irradiation on fibronectin. AKT, GSK-3␤-cyclin D1, mitogen-activated protein kinase kinase 1/2-mitogen-activated protein kinase, and c-Jun NH 2 -terminal kinase signaling was dysregulated in irradiated ILK-hk mutants. Immunofluorescence stainings of ILK-hk cells indicated disturbed ILK and paxillin membrane localization with concomitant decrease in focal adhesions. Profound ILK-hk-dependent changes in morphology were characterized by spindle-like cell shape, cell size reduction, increased cell protrusions, strong formation of membranous f-actin rings, and significantly reduced adhesion to matrix proteins. Additionally, ILK-wk and ILK-hk overexpression impaired ␤1-integrin clustering and protein Tyr-phosphorylation. Taken together, the data provide evidence that ILK signaling modulates the cellular radiation response involving diverse signaling pathways and through changes in f-actin-based processes such as focal adhesion formation, cell adhesion, and spreading. Identification of ILK and its signaling partners as potential targets for tumor radiosensitization might promote innovative anticancer strategies by providing insight into the mechanism of cell adhesion-mediated radioresistance, oncogenic transformation, and tumor growth and spread.

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“…Perturbations of these filaments, spread all over the cell, can in fact overexpose intracellular components allowing these biomolecules to absorb more radiation and, consequently, to present higher basal damage. Is known for several years that Cytochalasin B, a drug that prevents the actin polymerization, increases radiosensitivity to ionizing radiation in a ECM-dependent manner (Stevenson and Lange, 1997). Disruption of the actin network also impairs the transport of actin-dependent proteins and organelles, affecting the transport of proteins/complexes involved in DNA damage response and repair, as well as those involved in chromatin remodeling.…”

Section: Discussionmentioning

confidence: 99%

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

Magalhães

Silva

Osaki

et al. 2020

Front. Cell Dev. Biol.

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Typical Rho GTPases include the enzymes RhoA, Rac1, and Cdc42 that act as molecular switches to regulate essential cellular processes in eukaryotic cells such as actomyosin dynamics, cell cycle, adhesion, death and differentiation. Recently, it has been shown that different conditions modulate the activity of these enzymes, but their functions still need to be better understood. Here we examine the interplay between RhoA and the NER (Nucleotide Excision Repair) pathway in human cells exposed to UVA, UVB or UVC radiation. The results show high levels and accumulation of UV-induced DNA lesions (strand breaks and cyclobutane pyrimidine dimers, CPDs) in different cells with RhoA loss of function (LoF), either by stable overexpression of negative dominant RhoA (RhoA-N19 mutant), by inhibition with C3 toxin or by transient silencing with siRNA. Cells under RhoA LoF showed reduced levels of γH2AX, p-Chk1 (Ser345) and p-p53 (Ser15) that reflected causally in their accumulation in G1/S phases, in low survival rates and in reduced cell proliferation, also in accordance with the energy of applied UV light. Even NER-deficient cells (XPA, XPC) or DNA translesion synthesis (TLS)-deficient cells (XPV) showed substantial hypersensitivity to UV effects when previously submitted to RhoA LoF. In contrast, analyses of apoptosis, necrosis, autophagy and senescence revealed that all cells displaying normal levels of active RhoA (RhoA-GTP) are more resistant to UV-promoted cell death. This work reaffirms the role of RhoA protein signaling in protecting cells from damage caused by UV radiation and demonstrates relevant communicating mechanisms between actin cytoskeleton and genomic stability.

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Extracellular Matrix (ECM) and Cytoskeletal Modulation of Cellular Radiosensitivity

Cited by 11 publications

References 12 publications

Cetuximab Attenuates Its Cytotoxic and Radiosensitizing Potential by Inducing Fibronectin Biosynthesis

Cetuximab Attenuates Its Cytotoxic and Radiosensitizing Potential by Inducing Fibronectin Biosynthesis

Overexpression of Hyperactive Integrin-Linked Kinase Leads to Increased Cellular Radiosensitivity

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

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