Dataset Information

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are ?3 Integrin-Dependent and Involve a Ca²⁺/P2X7 Receptor Signaling Axis.

ABSTRACT: Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca²⁺-dependent hemichannel opening, as well as the P2X7 receptor, are key players in Thy-1-?_V?₃ Integrin-induced migration of reactive astrocytes. Thus, we investigated whether this signaling pathway is activated in MDA-MB-231 breast cancer cells and in B16F10 melanoma cells when stimulated with Thy-1. In both cancer cell types, Thy-1 induced a rapid increase in intracellular Ca²⁺, ATP release, as well as cell migration and invasion. Connexin and Pannexin inhibitors decreased cell migration, implicating a requirement for hemichannel opening in Thy-1-induced cell migration. In addition, cell migration and invasion were precluded when the P2X7 receptor was pharmacologically blocked. Moreover, the ability of breast cancer and melanoma cells to transmigrate through an activated endothelial monolayer was significantly decreased when the ?₃ Integrin was silenced in these cancer cells. Importantly, melanoma cells with silenced ?₃ Integrin were unable to metastasize to the lung in a preclinical mouse model. Thus, our results suggest that the Ca²⁺/hemichannel/ATP/P2X7 receptor-signaling axis triggered by the Thy-1-?_V?₃ Integrin interaction is important for cancer cell migration, invasion and transvasation. These findings open up the possibility of therapeutically targeting the Thy-1-Integrin signaling pathway to prevent metastasis.

SUBMITTER: Brenet M

PROVIDER: S-EPMC7835543 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca<sup>2+</sup>/P2X7 Receptor Signaling Axis.

Brenet Marianne M Martínez Samuel S Pérez-Nuñez Ramón R Pérez Leonardo A LA Contreras Pamela P Díaz Jorge J Avalos Ana María AM Schneider Pascal P Quest Andrew F G AFG Leyton Lisette L

Frontiers in cell and developmental biology 20210112

Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca<sup>2+</sup>-dependent hemichannel opening, as well as the P2X7 receptor ...[more]

PMID: 33511115

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Project description:Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.

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Dataset Information

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are ?3 Integrin-Dependent and Involve a Ca²⁺/P2X7 Receptor Signaling Axis.

Publications

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca<sup>2+</sup>/P2X7 Receptor Signaling Axis.

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Dataset Information

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are ?3 Integrin-Dependent and Involve a Ca2+/P2X7 Receptor Signaling Axis.

Publications

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca<sup>2+</sup>/P2X7 Receptor Signaling Axis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are ?3 Integrin-Dependent and Involve a Ca²⁺/P2X7 Receptor Signaling Axis.