ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell–Endothelial Cell Interaction

Najy, Abdo J.; Day, Kathleen C.; Day, Mark L.

doi:10.1158/0008-5472.can-07-2432

Cited by 85 publications

(96 citation statements)

References 46 publications

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“…Consistent with the finding of decreased neovascularization, smaller tumors were formed in the ADAM-15 -deficient mice compared with control mice after injection with melanoma cells (37). More recently, Najy et al (38) found that down-regulation of ADAM-15 in the prostate cancer cell line PC3 decreased migration and adhesion to specific extracellular protein matrix proteins, such as fibronectin, vitronectin, and laminin. In vivo, loss of ADAM-15 decreased metastasis to bone.…”

Section: Evidence Of a Role For Adams In Cancersupporting

confidence: 70%

Role of ADAMs in Cancer Formation and Progression

Duffy

McKiernan

O’Donovan

et al. 2009

Clinical Cancer Research

198

199

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The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. One of their best-established roles is the release of biologically important ligands, such as tumor necrosis factor^a, epidermal growth factor, transforming growth factor^a, and amphiregulin. Because these ligands have been implicated in the formation and progression of tumors, it might be expected that the specific ADAMs involved in their release would also be involved in malignancy. Consistent with this hypothesis, emerging data from model systems suggest that ADAMs, such as ADAM-9, ADAM-12, ADAM-15, and ADAM-17, are causally involved in tumor formation/progression. In human cancer, specific ADAMs are upregulated, with levels generally correlating with parameters of tumor progression and poor outcome. In preclinical models, selective ADAM inhibitors against ADAM-10 and ADAM-17 have been shown to synergize with existing therapies in decreasing tumor growth.TheADAMs are thus a new family of potential targets for the treatment of cancer, especially malignancies that are dependent on human epidermal growth factor receptor ligands or tumor necrosis factor^a.

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Section: Evidence Of a Role For Adams In Cancersupporting

confidence: 70%

Role of ADAMs in Cancer Formation and Progression

Duffy

McKiernan

O’Donovan

et al. 2009

Clinical Cancer Research

198

199

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“…Another potential target for miR-1247 is FosB, which dimerizes with Jun protein to activate transcription of proteases involved in tumor migration and invasion [34]. Finally, the transmembrane glycoprotein, ADAM15, might also be targeted by miR-1247, to facilitate prostate cancer metastasis [35]. These computationally predicted targets will need to be empirically validated in the future.…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Analysis of Epigenetically Silenced MicroRNAs in Colorectal Cancer Cells

et al. 2011

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Abnormal microRNA (miRNA) expression has been linked to the development and progression of several human cancers, and such dysregulation can result from aberrant DNA methylation. While a small number of miRNAs is known to be regulated by DNA methylation, we postulated that such epigenetic regulation is more prevalent. By combining MBD-isolated Genome Sequencing (MiGS) to evaluate genome-wide DNA methylation patterns and microarray analysis to determine miRNA expression levels, we systematically searched for candidate miRNAs regulated by DNA methylation in colorectal cancer cell lines. We found 64 miRNAs to be robustly methylated in HCT116 cells; eighteen of them were located in imprinting regions or already reported to be regulated by DNA methylation. For the remaining 46 miRNAs, expression levels of 18 were consistent with their DNA methylation status. Finally, 8 miRNAs were up-regulated by 5-aza-2′-deoxycytidine treatment and identified to be novel miRNAs regulated by DNA methylation. Moreover, we demonstrated the functional relevance of these epigenetically silenced miRNAs by ectopically expressing select candidates, which resulted in inhibition of growth and migration of cancer cells. In addition to reporting these findings, our study also provides a reliable, systematic strategy to identify DNA methylation-regulated miRNAs by combining DNA methylation profiles and expression data.

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“…Furthermore, suppression of ADAM15 led to enhanced TLR3-and TLR4-mediated production of proinflammatory cytokines and chemokines. Several MMPs, including MMP-3 and MMP-9, contain NF-kB and AP2 transcription factor binding sites within their promoters, indicating that they may be induced during inflammatory episodes, and studies have shown that they may be modulated by ADAMs (23,51). Moreover, poly(I:C) and LPS have been shown to induce MMP-1, MMP-3, MMP-10, and MMP-13 expression in lung epithelial cells and chondrocytes (6,52,53).…”

Section: Discussionmentioning

confidence: 99%

“…4C-E). It has been reported that MMP-9 secretion and activity were abolished in the metastatic prostate cancer PC-3 cell line following suppression of ADAM15 expression (23). Furthermore, ADAM15 has been shown to cleave the ectodomain of MMP-10 (24).…”

Section: Suppression Of Adam15 Expression Enhances Proinflammatory Cymentioning

confidence: 99%

TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

Ahmed

Maratha

Butt

et al. 2013

The Journal of Immunology

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TLRs are a group of pattern-recognition receptors that play a crucial role in danger recognition and induction of the innate immune response against bacterial and viral infections. The TLR adaptor molecule, Toll/IL-1R domain-containing adaptor inducing IFN (TRIF), facilitates TLR3 and TLR4 signaling and concomitant activation of the transcription factors, NF-κB and IFN regulatory factor 3, leading to proinflammatory cytokine production. Whereas numerous studies have been undertaken toward understanding the role of TRIF in TLR signaling, little is known about the signaling components that regulate TRIF-dependent TLR signaling. To this end, TRIF-interacting partners were identified by immunoprecipitation of the TRIF signaling complex, followed by protein identification using liquid chromatography mass spectrometry. Following stimulation of cells with a TLR3 or TLR4 ligand, we identified a disintegrin and metalloprotease (ADAM)15 as a novel TRIF-interacting partner. Toward the functional characterization of the TRIF:ADAM15 interaction, we show that ADAM15 acts as a negative regulator of TRIF-mediated NF-κB and IFN-β reporter gene activity. Also, suppression of ADAM15 expression enhanced polyriboinosinic polyribocytidylic acid and LPS-mediated proinflammatory cytokine production via TRIF. In addition, suppression of ADAM15 expression enhanced rhinovirus 16 and vesicular stomatitis virus–mediated proinflammatory cytokine production. Interestingly, ADAM15 mediated the proteolytic cleavage of TRIF. Thus, ADAM15 serves to curtail TRIF-dependent TLR3 and TLR4 signaling and, in doing so, protects the host from excessive production of proinflammatory cytokines and matrix metalloproteinases. In conclusion, to our knowledge, our study clearly shows for the first time that ADAM15 plays an unexpected role in TLR signaling, acting as an anti-inflammatory molecule through impairment of TRIF-mediated TLR signaling.

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ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell–Endothelial Cell Interaction

Cited by 85 publications

References 46 publications

Role of ADAMs in Cancer Formation and Progression

Role of ADAMs in Cancer Formation and Progression

Identification and Functional Analysis of Epigenetically Silenced MicroRNAs in Colorectal Cancer Cells

TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

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