scholarly journals Targeting Raf Kinase Inhibitory Protein Regulation and Function

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 306 ◽  
Author(s):  
Ali Yesilkanal ◽  
Marsha Rosner
Keyword(s):  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Signaling Networks ◽  
Metastasis Suppressor ◽  
Metastatic Progression ◽  
Inhibitory Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitory Protein ◽  
And Function

Raf Kinase Inhibitory Protein (RKIP) is a highly conserved kinase inhibitor that functions as a metastasis suppressor in a variety of cancers. Since RKIP can reprogram tumor cells to a non-metastatic state by rewiring kinase networks, elucidating the mechanism by which RKIP acts not only reveals molecular mechanisms that regulate metastasis, but also represents an opportunity to target these signaling networks therapeutically. Although RKIP is often lost during metastatic progression, the mechanism by which this occurs in tumor cells is complex and not well understood. In this review, we summarize our current understanding of RKIP regulation in tumors and consider experimental and computational strategies for recovering or mimicking its function by targeting mediators of metastasis.

scholarly journals Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 442 ◽  
Author(s):  
Ana Raquel-Cunha ◽  
Diana Cardoso-Carneiro ◽  
Rui M. Reis ◽  
Olga Martinho
Keyword(s):  
Lung Cancer ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Egfr Inhibitors ◽  
Current Status ◽  
Tyrosine Kinase Domain ◽  
Metastasis Suppressor ◽  
Inhibitory Protein ◽  
Suppressor Activity ◽  
Raf Kinase

Lung cancer is the most deadly neoplasm with the highest incidence in both genders, with non-small cell lung cancer (NSCLC) being the most frequent subtype. Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are key drivers of NSCLC progression, with EGFR inhibitors being particularly beneficial for patients carrying the so-called “EGFR-sensitizing mutations”. However, patients eventually acquire resistance to these EGFR inhibitors, and a better knowledge of other driven and targetable proteins will allow the design of increasingly accurate drugs against patients’ specific molecular aberrations. Raf kinase inhibitory protein (RKIP) is an important modulator of relevant intracellular signaling pathways, including those controlled by EGFR, such as MAPK. It has been reported that it has metastasis suppressor activity and a prognostic role in several solid tumors, including lung cancer. In the present review, the potential use of RKIP in the clinic as a prognostic biomarker and predictor of therapy response in lung cancer is addressed.

Raf kinase inhibitor protein: mechanism of loss of expression and association with genomic instability

2008 ◽  
Vol 61 (4) ◽  
pp. 524-529 ◽  
Author(s):  
F Al-Mulla ◽  
S Hagan ◽  
W Al-Ali ◽  
S P Jacob ◽  
A I Behbehani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chromosomal Instability ◽  
Cultured Cells ◽  
Kinase Inhibitor ◽  
Methylation Status ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Metastasis Suppressor ◽  
Metastatic Progression ◽  
Raf Kinase

Aims:Raf kinase inhibitory protein (RKIP; also known as PEBP, for phosphatidylethanolamine-binding protein) is an endogenous inhibitor of the Raf– MAPK kinase (MEK)–MAP kinase pathway. It has emerged as a significant metastasis suppressor in a variety of human cancers including colorectal cancer (CRC) and was recently shown to regulate the spindle checkpoint in cultured cells. This study aims at correlating RKIP expression with chromosomal instability in colorectal cancer samples and identifies possible mechanisms of RKIP loss.Methods:Chromosomal instability was assessed using metaphase-based comparative genomic hybridisation (CGH) and loss of heterozygosity (LOH) in 65 cases with microsatellite stable CRC and correlated with RKIP expression. Methyl-specific PCR was used on DNA extracted from 82 cases with CRC to determine CpG methylation status at the RKIP promoter and the results correlated with RKIP protein expression.Results:We demonstrate for the first time that in microsatellite stable (MSS) CRC, the number of chromosomal losses is inversely proportional to RKIP expression levels. We also show that methylation of the RKIP promoter is a major mechanism by which RKIP expression is silenced in CRC.Conclusions:RKIP loss by hypermethylation of its promoter could have a significant influence on colorectal cancer aneuploidy, which might explain its association with metastatic progression.

Abstract 3251: Regulation of TNBC kinome by the metastasis suppressor Raf kinase inhibitory protein (RKIP)

2015 ◽  
Author(s):  
Ali E. Yesilkanal ◽  
Casey Frankenberger ◽  
Daniel Rabe ◽  
Gary L. Johnson ◽  
Marsha R. Rosner
Keyword(s):  
Metastasis Suppressor ◽  
Inhibitory Protein ◽  
Raf Kinase ◽  
Raf Kinase Inhibitory Protein

scholarly journals Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gautier Follain ◽  
Naël Osmani ◽  
Valentin Gensbittel ◽  
Nandini Asokan ◽  
Annabel Larnicol ◽  
...  
Keyword(s):  
Blood Flow ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Metastatic Progression ◽  
Metastatic Dissemination ◽  
Secondary Tumors ◽  
Flow Profiles ◽  
Endothelial Response ◽  
Life Threatening

AbstractTumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified pro-metastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis of endothelial cells revealed that blood flow enhanced VEGFR signaling, among others. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented upon specific inhibition of VEGFR tyrosine kinase and subsequent signaling. Inhibitory targeting of VEGFRs reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of VEGFR-dependent endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.

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