EphA2 bears plasticity to tumor invasion

Sugiyama, Nami; Gucciardo, Erika; Lehti, Kaisa

doi:10.4161/cc.26180

Cited by 6 publications

(5 citation statements)

References 8 publications

(25 reference statements)

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“…Here, we demonstrated that suppression of ABCA1 activity by the combination of EPA with EPHA2 inhibition induced the accumulation of cellular cholesterol, contributing to increased membrane polarity, inhibition of SREBP2, disruption of cellular lipid homeostasis, and apoptosis ( Figure 4K ). Supporting our conclusions are recent studies that suggest that inhibition of either ABCA1 or EPHA2 can alter cell membrane polarity, leading to decreased metastatic potential 32 , 40 , 41 . Further, ABCA1 overexpression was associated with poor prognosis in breast, ovarian, and hepatocellular carcinomas 40 , 42 , 43 , which suggests that an EPA-based combination therapy may be effective in other EPHA2-positive cancers which broadens the impact of this study.…”

Section: Discussionsupporting

confidence: 88%

“…Our strategy of targeting EPHA2 in conjunction with EPA therapy was shown to be effective through a novel, membrane-based mechanism that controls cell viability. Cell-surface-localized EPHA2 has been implicated in the control of gap junctions and cell plasma membrane polarity, subsequently contributing to tumor migration and invasion 32 , 33 . Further, EPA, when incorporated into the plasma membrane, can modify lipid rafts, increase membrane compaction, modify intracellular signaling, and inhibit invasive potential 16 , 34 , 35 .…”

Section: Discussionmentioning

confidence: 99%

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Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Torres-Adorno

Vitrac

et al. 2018

Oncogene

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Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, currently lacks effective targeted therapy options. Eicosapentaenoic acid (EPA), an omega-3 fatty acid and constituent of fish oil, is a common supplement with anti-inflammatory properties. Although it is not a mainstream treatment, several preclinical studies have demonstrated that EPA exerts anti-tumor activity in breast cancer. However, against solid tumors, EPA as a monotherapy is clinically ineffective; thus, we sought to develop a novel targeted drug combination to bolster its therapeutic action against TNBC. Using a high-throughput functional siRNA screen, we identified Ephrin type-A receptor 2 (EPHA2), an oncogenic cell-surface receptor tyrosine kinase, as a therapeutic target that sensitizes TNBC cells to EPA. EPHA2 expression was uniquely elevated in TNBC cell lines and patient tumors. In independent functional expression studies in TNBC models, EPHA2 gene-silencing combined with EPA significantly reduced cell growth and enhanced apoptosis compared with monotherapies, both in vitro and in vivo. EPHA2 specific inhibitors similarly enhanced the therapeutic action of EPA. Finally, we identified that therapy-mediated apoptosis was attributed to a lethal increase in cancer cell membrane polarity due to ABCA1 inhibition and subsequent dysregulation of cholesterol homeostasis. This study provides new molecular and pre-clinical evidence to support a clinical evaluation of EPA combined with EPHA2 inhibition in patients with TNBC.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Torres-Adorno

Vitrac

et al. 2018

Oncogene

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“…MT1-MMP sheds additional cell surface biomolecules, such as syndecan-1 [72], MHC class I chain-related molecule A (see below) [73], E-cadherin (see below) [74], low-density lipoprotein receptor-related protein 1 (LRP1/CD91) [75], mucin 1 [76], and tissue trans -glutaminase [77], and processes cytokines, chemokines, and growth factors, such as the pro-tumor necrosis factor [22]. The receptor Tyr kinase erythropoietin producing hepatocellular A2 (EphA2) is cleaved by MT1-MMP [78,79,80]. Cleavage at the Gly391-Leu392 bond promoted EphA2 internalization and single cell breast carcinoma invasion [78,79], while cleavage at Ser432-Tyr433 promoted ligand-independent activation of RhoG by EphA2 and epidermoid carcinoma cell migration [80].…”

Section: Activities Of Mt1-mmpmentioning

confidence: 99%

“…The receptor Tyr kinase erythropoietin producing hepatocellular A2 (EphA2) is cleaved by MT1-MMP [78,79,80]. Cleavage at the Gly391-Leu392 bond promoted EphA2 internalization and single cell breast carcinoma invasion [78,79], while cleavage at Ser432-Tyr433 promoted ligand-independent activation of RhoG by EphA2 and epidermoid carcinoma cell migration [80].…”

Section: Activities Of Mt1-mmpmentioning

confidence: 99%

The Expanding Role of MT1-MMP in Cancer Progression

Knapinska

Fields

2019

Pharmaceuticals

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For over 20 years, membrane type 1 matrix metalloproteinase (MT1-MMP) has been recognized as a key component in cancer progression. Initially, the primary roles assigned to MT1-MMP were the activation of proMMP-2 and degradation of fibrillar collagen. Proteomics has revealed a great array of MT1-MMP substrates, and MT1-MMP selective inhibitors have allowed for a more complete mapping of MT1-MMP biological functions. MT1-MMP has extensive sheddase activities, is both a positive and negative regulator of angiogenesis, can act intracellularly and as a transcription factor, and modulates immune responses. We presently examine the multi-faceted role of MT1-MMP in cancer, with a consideration of how the diversity of MT1-MMP behaviors impacts the application of MT1-MMP inhibitors.

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“…Indeed, a critical role for EphA2 in epithelial tumor metastases and invasiveness is well-studied. 38,49,55 Our data suggest that GPRC5A may be involved in tumor progression due to its role in cell-matrix adhesion and, possibly, in association with EphA2 receptor.…”

Section: Discussionmentioning

confidence: 57%

Orphan G protein-coupled receptor GPRC5A modulates integrin β1-mediated epithelial cell adhesion

Bulanova

Akimov

Rokka

et al. 2017

Cell Adhesion & Migration

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G-Protein Coupled Receptor (GPCR), Class C, Group 5, Member A (GPRC5A) has been implicated in several malignancies. The underlying mechanisms, however, remain poorly understood. Using a panel of human cell lines, we demonstrate that CRISPR/Cas9-mediated knockout and RNAi-mediated depletion of GPRC5A impairs cell adhesion to integrin substrates: collagens I and IV, fibronectin, as well as to extracellular matrix proteins derived from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma (Matrigel). Consistent with the phenotype, knock-out of GPRC5A correlated with a reduced integrin β1 (ITGB1) protein expression, impaired phosphorylation of the focal adhesion kinase (FAK), and lower activity of small GTPases RhoA and Rac1. Furthermore, we provide the first evidence for a direct interaction between GPRC5A and a receptor tyrosine kinase EphA2, an upstream regulator of FAK, although its contribution to the observed adhesion phenotype is unclear. Our findings reveal an unprecedented role for GPRC5A in regulation of the ITGB1-mediated cell adhesion and it's downstream signaling, thus indicating a potential novel role for GPRC5A in human epithelial cancers.

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EphA2 bears plasticity to tumor invasion

Cited by 6 publications

References 8 publications

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

The Expanding Role of MT1-MMP in Cancer Progression

Orphan G protein-coupled receptor GPRC5A modulates integrin β1-mediated epithelial cell adhesion

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