Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress

Tolbert, Caitlin E.; Beck, Matthew V.; Kilmer, Claire E.; Srougi, Melissa C.

doi:10.1016/j.bbrc.2018.12.033

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…It has been shown that Atm deficiency leads to oxidative stress, especially in the cerebellum (Kamsler et al, 2001; Stern et al, 2002). Elevated ROS levels due to Atm loss are involved in increased cell migration through Rac1 activation; oxidative stress directly activates Rac1 resulting in cytoskeleton reorganization (Tolbert et al, 2019). To evaluate the connection between cell migration and oxidative stress, we analyzed the ROS levels in WT and Atm −/− microglia derived from the cerebellum and the cerebral cortex.…”

Section: Resultsmentioning

confidence: 99%

“…Two main mechanisms may result in this phenomenon: First, we speculate that increased levels of ROS and reactive nitrogen species that we observed in Atm À/À cerebellar microglia compared to WT cells (Figure 7) accelerate microglial motility. It has been shown that elevated levels of these reactive species directly increase the steadystate levels of GTP-bound Rac1 protein thereby accelerating motility (Tolbert et al, 2019). Second, microglia in their resting state are not motile but rather actively survey their environment through their highly motile processes and protrusions (Nimmerjahn et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Dysfunction of cerebellar microglia in Ataxia‐telangiectasia

Levi

Bar

Cohen-Adiv

et al. 2021

Glia

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Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging. ATM phosphorylates more than 1500 target proteins, which are involved in cell cycle control, DNA repair, apoptosis, modulation of chromatin structure, and other cytoplasmic as well as mitochondrial processes. In our quest to better understand the mechanisms

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dysfunction of cerebellar microglia in Ataxia‐telangiectasia

Levi

Bar

Cohen-Adiv

et al. 2021

Glia

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“…This seems to be mediated by direct Rac1 oxidation on Cys18 at the catalytic site as a Cys-Ser mutant did not show any activation in response to H 2 O 2 treatment (Heo and Campbell, 2005). While the specific redox modification of Rac1 was previously only associated with the formation of lamellipodia (Hobbs et al, 2014), Rac1-mediated ROS production by NOXes has been attributed to several functions including cell migration (Myant et al, 2013;Tolbert et al, 2019).…”

Section: Rho Gtpasesmentioning

confidence: 98%

Redox Regulation of the Actin Cytoskeleton in Cell Migration and Adhesion: On the Way to a Spatiotemporal View

Balta

Kramer

Samstag

2021

Front. Cell Dev. Biol.

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The actin cytoskeleton of eukaryotic cells is a dynamic, fibrous network that is regulated by the concerted action of actin-binding proteins (ABPs). In particular, rapid polarization of cells in response to internal and external stimuli is fundamental to cell migration and invasion. Various isoforms of ABPs in different tissues equip cells with variable degrees of migratory and adhesive capacities. In addition, regulation of ABPs by posttranslational modifications (PTM) is pivotal to the rapid responsiveness of cells. In this context, phosphorylation of ABPs and its functional consequences have been studied extensively. However, the study of reduction/oxidation (redox) modifications of oxidation-sensitive cysteine and methionine residues of actin, ABPs, adhesion molecules, and signaling proteins regulating actin cytoskeletal dynamics has only recently emerged as a field. The relevance of such protein oxidations to cellular physiology and pathophysiology has remained largely elusive. Importantly, studying protein oxidation spatiotemporally can provide novel insights into localized redox regulation of cellular functions. In this review, we focus on the redox regulation of the actin cytoskeleton, its challenges, and recently developed tools to study its physiological and pathophysiological consequences.

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“…A vast amount of literature suggest an inextricable relationship between RAC1 and ROS. Some articles suggest that changes in RAC1 are a prerequisite for changes in ROS (45)(46)(47)(48), whereas other studies found that changes in ROS affect RAC1 activity (49,50). Regarding the effect of tigecycline, there is no data in the literature about the effect of tigecycline on RAC1 and not much data about the relationship between tigecycline and ROS.…”

Section: Discussionmentioning

confidence: 99%

Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells

Koch

Beirith

et al. 2023

Preprint

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Background: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by underlying liver disease and a shortage of organ donors. Especially after LR, we are dealing with high recurrence rates, and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed at investigating the effect of tigecycline on HCC cell lines and its mechanisms of action. Methods: Huh7, HepG2 cells, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot and RT-PCR. 2',7'-dichlorofluorescein diacetate (DCFH-DA) was utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment. FACS was used to detect alterations in the cell cycle and changes in mitochondrial function were detected via seahorse analysis. Results: Tigecycline treatment resulted in a significant reduction of mitochondrial function, which preceded the observed loss of HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes, indicating a selective antitumoral efficacy. Tigecycline inhibited both migration and invasion. Bioinformatic analysis identified RAC1 as a possible target for tigecycline and the expression of this molecule was increased in both HCC as a result of tigecycline treatment. Tigecycline also caused decreased ROS production and an S-phase cell cycle arrest. Conclusion: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced OXPHOS, is associated with increased expression of RAC1. The selective effect of tigecycline on HCC cells versus normal hepatocytes represents the rationale for the possible use of this agent in cancer treatment.

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Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress

Cited by 8 publications

References 23 publications

Dysfunction of cerebellar microglia in Ataxia‐telangiectasia

Dysfunction of cerebellar microglia in Ataxia‐telangiectasia

Redox Regulation of the Actin Cytoskeleton in Cell Migration and Adhesion: On the Way to a Spatiotemporal View

Tigecycline causes loss of cell viability mediated by mitochondrial OXPHOS and RAC1 in hepatocellular carcinoma cells

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