Stiffening of DU145 prostate cancer cells driven by actin filaments – microtubule crosstalk conferring resistance to microtubule-targeting drugs

Kubiak, Andrzej; Chighizola, Matteo; Schulte, Carsten; Bryniarska, Natalia; Wesołowska, Julita; Pudełek, Maciej; Lasota, Małgorzata; Ryszawy, Damian; Basta‐Kaim, Agnieszka; Laidler, Piotr; Podestà, Alessandro; Lekka, Małgorzata

doi:10.1039/d0nr06464e

Cited by 26 publications

(27 citation statements)

References 87 publications

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“…Cell adhesion features already play an important role in various cancer treatments. Recently Kubiak et al 69 demonstrated that treatment with microtubule-targeting antimitotic drugs, such as vinca alkaloids and taxanes, can change actin cytoskeletal organization and cell mechanics, influencing drug resistance. Another study highlighted that integrin-mediated cell adhesion can have an impact on cancer drug sensitivity 70 .…”

Section: Discussionmentioning

confidence: 99%

“…Since this is a short period of the cell cycle, the effect of a drug can be specific to the rapidly dividing tumor cells. Given the wide clinical use of vinca alkaloids and taxanes, currently, the microtubules represent the best target to date for cancer chemotherapy 69 . However, several clinical trials have proved integrins to be a promising therapeutic target to battle cancer cells, though no specific drug was found to be exceptionally effective 71 .…”

Section: Discussionmentioning

confidence: 99%

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Single-cell adhesion strength and contact density drops in the M phase of cancer cells

Ungai-Salánki

Haty

Gerecsei

et al. 2021

Sci Rep

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The high throughput, cost effective and sensitive quantification of cell adhesion strength at the single-cell level is still a challenging task. The adhesion force between tissue cells and their environment is crucial in all multicellular organisms. Integrins transmit force between the intracellular cytoskeleton and the extracellular matrix. This force is not only a mechanical interaction but a way of signal transduction as well. For instance, adhesion-dependent cells switch to an apoptotic mode in the lack of adhesion forces. Adhesion of tumor cells is a potential therapeutic target, as it is actively modulated during tissue invasion and cell release to the bloodstream resulting in metastasis. We investigated the integrin-mediated adhesion between cancer cells and their RGD (Arg-Gly-Asp) motif displaying biomimetic substratum using the HeLa cell line transfected by the Fucci fluorescent cell cycle reporter construct. We employed a computer-controlled micropipette and a high spatial resolution label-free resonant waveguide grating-based optical sensor calibrated to adhesion force and energy at the single-cell level. We found that the overall adhesion strength of single cancer cells is approximately constant in all phases except the mitotic (M) phase with a significantly lower adhesion. Single-cell evanescent field based biosensor measurements revealed that at the mitotic phase the cell material mass per unit area inside the cell-substratum contact zone is significantly less, too. Importantly, the weaker mitotic adhesion is not simply a direct consequence of the measured smaller contact area. Our results highlight these differences in the mitotic reticular adhesions and confirm that cell adhesion is a promising target of selective cancer drugs as the vast majority of normal, differentiated tissue cells do not enter the M phase and do not divide.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Single-cell adhesion strength and contact density drops in the M phase of cancer cells

Ungai-Salánki

Haty

Gerecsei

et al. 2021

Sci Rep

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“…Immunofluorescent staining and confocal imaging were performed as described previously [ 50 ]. Briefly, microglial cells were seeded on glass coverslips in 24-well plates.…”

Section: Methodsmentioning

confidence: 99%

Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways

Tylek

Trojan

Leśkiewicz

et al. 2021

Cells

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Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed after 24 h of stimulation by endotoxin. MR-39 was the only FPR2 ligand that attenuated LPS-evoked changes in the mitochondrial membrane potential and diminished the ROS and NO release. Moreover, the LPS-induced alterations in the microglial phenotype were modulated by LXA4, AT-LXA4, and MR-39. The anti-inflammatory effect of MR-39 on the IL-1β release was mediated through FPR2. All tested ligands inhibited TNF-α production, while AT-LXA4 and MR-39 also diminished IL-6 levels in LPS-stimulated microglia. The favorable action of LXA4 and MR-39 was mediated through the inhibition of ERK1/2 phosphorylation. AT-LXA4 and MR39 diminished the phosphorylation of the transcription factor NF-κB, while AT-LXA4 also affected p38 kinase phosphorylation. Our results suggest that new pro-resolving synthetic mediators can represent an attractive treatment option for the enhancement of RoI, and that FPR2 can provide a perspective as a target in immune-related brain disorders.

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“…Initially, numerous experiments were focused on cancer biology, indicating the general conclusion that cancer cells are softer than their healthy counterparts, while for tissue, the opposite trend was observed [61,64]. Recently, AFM has been utilized to show that prostate cancer cells stiffen after treatment with chemotherapeutic agents such as cisplatin or microtubule interacting drugs [25,65]. Studies in this area reveal the significance of mechanical changes in cancer progression and provide a more in-depth explanation of pathogenesis as well as cellular response to treatment.…”

Section: Atomic Force Microscopymentioning

confidence: 99%

The emerging role of mechanical and topographical factors in the development and treatment of nervous system disorders: dark and light sides of the force

et al. 2021

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Nervous system diseases are the subject of intensive research due to their association with high mortality rates and their potential to cause irreversible disability. Most studies focus on targeting the biological factors related to disease pathogenesis, e.g. use of recombinant activator of plasminogen in the treatment of stroke. Nevertheless, multiple diseases such as Parkinson’s disease and Alzheimer’s disease still lack successful treatment. Recently, evidence has indicated that physical factors such as the mechanical properties of cells and tissue and topography play a crucial role in homeostasis as well as disease progression. This review aims to depict these factors’ roles in the progression of nervous system diseases and consequently discusses the possibility of new therapeutic approaches. The literature is reviewed to provide a deeper understanding of the roles played by physical factors in nervous system disease development to aid in the design of promising new treatment approaches. Graphic abstract

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Stiffening of DU145 prostate cancer cells driven by actin filaments – microtubule crosstalk conferring resistance to microtubule-targeting drugs

Abstract: The crucial role of microtubules in the mitotic-related segregation of chromosomes makes them an excellent target for anticancer microtubule targeting drugs (MTDs) such as, e.g., vinflunine (VFL), colchicine (COL), and...

Cited by 26 publications

References 87 publications

Single-cell adhesion strength and contact density drops in the M phase of cancer cells

Single-cell adhesion strength and contact density drops in the M phase of cancer cells

Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways

The emerging role of mechanical and topographical factors in the development and treatment of nervous system disorders: dark and light sides of the force

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