MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types

McAuley, J. Randall; Bailey, Kelly M.; Ekambaram, Prasanna; Klei, Linda R.; Kang, Hongjun; Hu, Dong; Freeman, Tanner J.; Concel, Vincent J.; Hubel, Nathaniel E.; Lee, Jia-Ying; Klei, Hanna B.; Cheng, Jing; Sekar, Preethiya; Bridwell, Rachel E.; Covic, Lidija; Lucas, Peter C.; McAllister-Lucas, Linda M.

doi:10.1038/s41388-019-0958-4

Cited by 26 publications

(21 citation statements)

References 70 publications

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“…Our group showed that ARRDC3 regulates trafficking of protease-activated receptor 1 (PAR1, also known as F2R; Arakaki et al, 2018a;Dores et al, 2015), a G-protein-coupled receptor (GPCR) implicated in breast cancer progression. PAR1 expression is markedly increased in breast cancer biopsies and correlates with metastasis and poor prognosis (Arakaki et al, 2018b;McAuley et al, 2019). Overexpression of PAR1 also occurs in TNBC, owing, in part, to defective lysosomal trafficking, resulting in persistent signaling, cellular invasion and tumor growth (Arakaki et al, 2018a;Arora et al, 2008;Booden et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

Arakaki

Pan

Wedegaertner

et al. 2021

Journal of Cell Science

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The α-arrestin domain containing protein-3 (ARRDC3) is a tumor suppressor in triple-negative breast carcinoma (TNBC), a highly metastatic subtype of breast cancer which lacks targeted therapies. Thus, understanding the mechanisms and targets of ARRDC3 in TNBC is important. ARRDC3 regulates trafficking of protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis. Loss of ARRDC3 causes overexpression of PAR1 and aberrant signaling. Moreover, dysregulation of GPCR-induced Hippo signaling is associated with breast cancer progression. However, the mechanisms responsible for Hippo dysregulation remain unknown. Here, we report that the Hippo pathway transcriptional co-activator TAZ is the major effector of GPCR signaling and is required for TNBC migration and invasion. Additionally, ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, which occurs independent of ARRDC3-regulated PAR1 trafficking. The ARRDC3 C-terminal PPXY motifs and TAZ WW domain are critical for this interaction and required for suppression of TNBC migration and lung metastasis in vivo. These studies are the first to demonstrate a role for ARRDC3 in regulating GPCR-induced TAZ activity in TNBC and reveal multi-faceted tumor suppressor functions of ARRDC3.

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Section: Introductionmentioning

confidence: 99%

α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

Arakaki

Pan

Wedegaertner

et al. 2021

Journal of Cell Science

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“…Notably, in patients with high expression of CTCFL, low levels of MALT1 indicate a good prognosis (OS and DSS). Previous studies report that MALT1 is a key regulator of chemoresistance in other cancer types 72 . This supports the idea that MALT1 may be utilized as a biomarker of chemoresistance in combination with CTCFL .…”

Section: Discussionmentioning

confidence: 99%

CTCFL regulates the PI3K-Akt pathway and it is a target for personalized ovarian cancer therapy

Salgado-Albarrán

Späth²,

González‐Barrios

et al. 2022

npj Syst Biol Appl

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High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy due to the lack of reliable biomarkers, effective treatment, and chemoresistance. Improving the diagnosis and the development of targeted therapies is still needed. The molecular pathomechanisms driving HGSC progression are not fully understood though crucial for effective diagnosis and identification of novel targeted therapy options. The oncogene CTCFL (BORIS), the paralog of CTCF, is a transcriptional factor highly expressed in ovarian cancer (but in rarely any other tissue in females) with cancer-specific characteristics and therapeutic potential. In this work, we seek to understand the regulatory functions of CTCFL to unravel new target genes with clinical relevance. We used in vitro models to evaluate the transcriptional changes due to the presence of CTCFL, followed by a selection of gene candidates using de novo network enrichment analysis. The resulting mechanistic candidates were further assessed regarding their prognostic potential and druggability. We show that CTCFL-driven genes are involved in cytoplasmic membrane functions; in particular, the PI3K-Akt initiators EGFR1 and VEGFA, as well as ITGB3 and ITGB6 are potential drug targets. Finally, we identified the CTCFL targets ACTBL2, MALT1 and PCDH7 as mechanistic biomarkers to predict survival in HGSC. Finally, we elucidated the value of CTCFL in combination with its targets as a prognostic marker profile for HGSC progression and as putative drug targets.

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“…[17][18][19] PAR1, which is widely expressed in human cancers, promotes the transformation and adhesion of pancreatic cancer cells and the invasion and metastasis of oral adenocarcinoma, colon cancer and breast cancer cells. [20][21][22][23][24][25][26] PAR2 is closely related to the growth and invasion of nasopharyngeal cancer, breast cancer, gastric cancer, colon cancer, prostate cancer and pancreatic cancer. [27][28][29][30][31][32][33][34] PAR1 and PAR2 are upregulated in ESCC, and can be served as possible Loading [MathJax]/jax/output/CommonHTML/jax.js prognostic markers because their expression levels are closely linked with the stage of tumor.…”

Section: Discussionmentioning

confidence: 99%

PAR1 and PAR4 exert opposite effects on tumor growth and metastasis of esophageal squamous cell carcinoma via STAT3 and NF-κB signaling pathways

Zhao

Jin

et al. 2021

Preprint

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BackgroundEsophageal carcinogenesis is a multifactorial process in which genetic and environmental factors interact to activate intracellular signals, leading to the uncontrolled survival and growth of esophageal squamous cell carcinoma (ESCC) cells. The intracellular pathways of ESCC cells could be regulated by proteinase activated-receptors (PARs), which are comprised of four receptors (i.e., PAR-1, PAR-2, PAR-3, and PAR-4). Therefore, the function and possible mechanism of PAR1 and PAR4 in the progression of ECSS were explored.MethodsFirst, we detected the expression levels of PAR1 and PAR4 in 27 cases of ESCC tissue specimens and cell lines by RT-qPCR, IHC and western blot. Meanwhile, the correlation between PAR1/PAR4 expression level, clinicopathological characteristics, and disease free survival were analyzed. Then, we constructed PAR1/PAR4 knockdown cell models and investigated the role of PAR1/PAR4 knockdown on the proliferation, apoptosis, changes of calcium flow, and metastasis of ESCC cell via MTT, flow cytometry, transwell and wound healing assays in vitro. Further, an experimental metastasis model in vivo was established to explore the role of stable PAR1/PAR4 knockdown on the growth and metastasis of ESCC cells. Finally, the role of nSMase2 in the activation of NF-κB induced by PAR4 and the role of NF-κB and STAT3 signaling pathways in the PAR1/PAR4-mediated tumor promoting or suppressive functions were measured by immunoprecipitation, western blot and immunofluorescence.ResultsThe integrated results demonstrated the expression levels of PAR1 and PAR4 are inversely proportional in ESCC. PAR1 could potently enhance tumor growth and metastasis, while PAR4 had an inhibitory effect. Further, the co-activation of STAT3 and NF-κB is involved in the PAR1 activation-induced tumor promoting effect, while only NF-κB participates in the PAR4 activation-induced tumor inhibitory effect in ESCC. To be specific, FAK/PI3K/AKT/STAT3/NF-κB mediated PAR1 activation-induced tumor promoting effect and nSMase2/MAPK/NF-κB mediated PAR4 activation-induced tumor inhibitory effect. ConclusionsOverall, the study provided new insights into the potential implication of PAR1 and PAR4 in the pathogenesis of ESCC. Besides, FAK/PI3K/AKT/STAT3/NF-κB and nSMase2/MAPK/NF-κB pathways may be novel targets for regulating tumor growh and cancer matastasis in ESCC patients.

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MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types

Cited by 26 publications

References 70 publications

α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

CTCFL regulates the PI3K-Akt pathway and it is a target for personalized ovarian cancer therapy

PAR1 and PAR4 exert opposite effects on tumor growth and metastasis of esophageal squamous cell carcinoma via STAT3 and NF-κB signaling pathways

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