Protease-activated receptor 2 induces migration and promotes Slug-mediated epithelial-mesenchymal transition in lung adenocarcinoma cells

Tsai, Chung-Che; Chou, Yu‐Ting; Fu, Hua-Wen

doi:10.1016/j.bbamcr.2018.10.011

Cited by 22 publications

(16 citation statements)

References 71 publications

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“…There are numerous attempts in exploring therapeutic approaches for targeting EMT to overcome EGFR-TKI resistance, e.g., metformin, gene knockout or pharmacological inhibition of FGFR or a transcription factor, Twist1 (Li et al, 2014;Raoof et al, 2019;Yochum et al, 2019). Meanwhile, EMT can be triggered by PAR2 activation in lung cancer cells and inhibition of PAR2 can stimulate prevention of EMT and cell migration (Sun et al, 2018;Tsai et al, 2018). When NSCLC became resistance to gefitinib, EMT could not be blocked by gefitinib whereas addition of a PAR2 inhibitor notably sensitized gefitinib to up-regulate E-cadherin and downregulate vimentin, consequently overcoming EMT-related drug resistance (Figures 3F-K).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the EMT phenotype and dysregulation of bypass signaling could initiate gefitinib resistance in NCSLC (Weng et al, 2019), which are also highly associated with PAR2 activation (Tsai et al, 2018). Therefore, we studied cell signaling pathway and EMT in P2pal-18S and gefitinib-treated cells for exploring the underlying mechanism of PAR2 inhibition in sensitizing NSCLC cells to gefitinib.…”

Section: Protease-activated Receptor 2 Inhibitionmentioning

confidence: 98%

“…G protein-coupled receptors (GPCRs) as the most widely studied drug targets have been reported to exhibit a transactivation with EGFR, i.e., GPCR ligands can activate EGFR to stimulate downstream signaling 2 decades ago (Daub et al, 1996). Protease-activated receptor 2 (PAR2) as a GPCR itself can facilitate Ca 2+ , MEK/ERK, AKT, PI3K and mTOR signaling pathways to promote a variety of tumor cell functions (Huang et al, 2013;Jiang et al, 2018;Tsai et al, 2018;Pawar et al, 2019). Meanwhile, PAR2 can transactivate EGFR and subsequently trigger MEK/ERK or AKT signaling, cooperatively modulating cell migration, apoptosis or proliferation in colon (Darmoul et al, 2004), pancreatic (Shi et al, 2013), gastric (Caruso et al, 2006), lung (Michel et al, 2014) and ovarian cancers (Jiang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, PAR2 can transactivate EGFR and subsequently trigger MEK/ERK or AKT signaling, cooperatively modulating cell migration, apoptosis or proliferation in colon (Darmoul et al, 2004), pancreatic (Shi et al, 2013), gastric (Caruso et al, 2006), lung (Michel et al, 2014) and ovarian cancers (Jiang et al, 2020). PAR2 blockade can significantly impair cell migration and EMT via ERK signaling in lung cancer (Tsai et al, 2018) whereas the dysregulation of ERK signaling and EMT are considered as molecular mechanisms of gefitinib resistance in NSCLC (Tricker et al, 2015;Becker et al, 2019;Weng et al, 2019), suggesting the potential involvement of PAR2-mediated signaling in lung tumor progression and drug resistance. Notably, mutational activations of other RTKs have also been identified to initiate gefitinib resistance since these receptors can exhibit parallel signaling pathways required for NSCLC cell survival (Rotow and Bivona, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation

Jiang

Xin

et al. 2021

Front. Pharmacol.

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Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the in vivo study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Protease-activated Receptor 2 Inhibitionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation

Jiang

Xin

et al. 2021

Front. Pharmacol.

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“…Whether the functional selectivity towards the G q and G 12/13 vs. G i/o would represent a therapeutic advantage remains to be investigated. Indeed, although PAR2-mediated activation of G i/o has been involved in breast cancer cell chemokinesis 62 and lung adenocarcinoma cell lines migration 63 , this pathway has also been involved in expression induction of cyclooxygenase-2 64,65 , which displays protective functions in the gastrointestinal tract 66 .…”

Section: G-protein-dependent Signaling Pathways Activated By Par2mentioning

confidence: 99%

The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects

et al. 2020

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Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gαq and Gα12/13 activity and their downstream effectors, while having no effect on Gi/o signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.

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Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells

Zhou

Luo

2023

Advanced Science

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When circulating tumor cells (CTCs) travel in circulation, they can be killed by detachment‐induced anoikis and fluidic shear stress (SS)‐mediated apoptosis. Circulatory treatment, which can make CTCs detached but also generate SS, can increase metastasis of cancer cells. To identify SS‐specific mechanosensors without detachment impacts, a microfluidic circulatory system is used to generate arteriosus SS and compare transcriptome profiles of circulating lung cancer cells with suspended cells. Half of the cancer cells can survive SS damage and show higher invasion ability. Mesotrypsin (PRSS3), protease‐activated receptor 2 (PAR2), and the subunit of activating protein 1, Fos‐related antigen 1 (FOSL1), are upregulated by SS, and their high expression is responsible for promoting invasion and metastasis. SS triggers PRSS3 to cleave the N‐terminal inhibitory domain of PAR2 within 2 h. As a G protein‐coupled receptor, PAR2 further activates the Gαi protein to turn on the Src‐ERK/p38/JNK‐FRA1/cJUN axis to promote the expression of epithelial–mesenchymal transition markers, and also PRSS3, which facilitates metastasis. Enriched PRSS3, PAR2, and FOSL1 in human tumor samples and their correlations with worse outcomes reveal their clinical significance. PAR2 may serve as an SS‐specific mechanosensor cleavable by PRSS3 in circulation, which provides new insights for targeting metastasis‐initiating CTCs.

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Protease-activated receptor 2 induces migration and promotes Slug-mediated epithelial-mesenchymal transition in lung adenocarcinoma cells

Cited by 22 publications

References 71 publications

Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation

Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation

The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects

Shear Stress Drives the Cleavage Activation of Protease‐Activated Receptor 2 by PRSS3/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells

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