Special Issue "Targeting Raf Kinase Inhibitor Protein (RKIP) in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 December 2018

Special Issue Editor

Guest Editor
Dr. Kam C. Yeung

Department of Cancer Biology, University of Toledo, Health Science Campus (formerly Medical College of Ohio) Mail Stop 1010, Transverse Drive,Toledo, OH 43614-5804, USA
Website | E-Mail
Phone: 4193836658

Special Issue Information

Dear Colleagues,

Raf Kinase Inhibitor Protein (RKIP) is a physiologically-relevant modulator of Raf-MEK-Erk, and NF-κB signaling cascades. It has since been found to modulate several additional signaling pathways. The mechanisms by which RKIP inhibit Raf have been defined. The molecular mechanisms by which RKIP impinges on other signaling pathways remain underexplored. Through regulating key signaling cascades, RKIP prevents numerous pathological conditions including cancer progression and metastasis.

Expression of RKIP is significantly reduced in cancer metastases. Importantly, restoration of RKIP expression inhibited metastasis in cancer cells transplantation mouse models. The metastatic process is a complex cascade that consists of distinct steps. Specific classes of genes that either enhance or suppress the metastatic process have been identified. Gain-of-function mutations in enhancers and/or loss-of-function in suppressors are important events during the progression of cancers toward a metastatic phenotype. Others and we have identified RKIP as a member of the metastasis suppressor gene (MSG) family in prostate and breast cancers. Functionally, RKIP interfere with the metastasis cascade by regulating the activity of multiple metastasis genes. Published results support the concept that RKIP functions as a novel master regulator of metastasis and may represent a novel therapeutic target for patients afflicted with metastatic cancer.

Unlike other classical tumor suppressor genes, which usually have complete loss-of-function mutations in tumor cells, the expression levels of RKIP are decreased but remain detectable and the protein is functionally active. The presence of inducible active RKIP in cancer cells, its anti-tumorigenic functions, and its ability to regulate multiple metastasis genes therefore makes restoration of RKIP expression a key novel approach for therapeutic intervention.

RKIP expression is downregulated in multiple types of cancer. It has been shown that in established cancer cell lines, overexpression of transcription repressors or oncogenic miRNAs is the cause of downregulation of RKIP. Conceptually, one can restore RKIP expression by re-introducing a heterologous promoter controlled RKIP gene into cancer cells for expression, or by targeting the transcription repressors or miRNAs for inactivation. In this Special Issue of Cancers, we explore different options that one can employ to materialize the potential of targeting RKIP for anti-cancer metastasis therapy.

Dr. Kam C. Yeung
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Transcription regulators
  • Metastasis
  • miRNA
  • RKIP
  • Targeted Gene therapy

Published Papers (3 papers)

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Research

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Open AccessFeature PaperArticle Functional Linkage of RKIP to the Epithelial to Mesenchymal Transition and Autophagy during the Development of Prostate Cancer
Cancers 2018, 10(8), 273; https://doi.org/10.3390/cancers10080273
Received: 12 July 2018 / Revised: 2 August 2018 / Accepted: 15 August 2018 / Published: 16 August 2018
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Abstract
Raf kinase inhibitor protein (RKIP) plays a critical role in many signaling pathways as a multi-functional adapter protein. In particular, the loss of RKIP’s function in certain types of cancer cells results in epithelial to mesenchymal transition (EMT) and the promotion of cancer
[...] Read more.
Raf kinase inhibitor protein (RKIP) plays a critical role in many signaling pathways as a multi-functional adapter protein. In particular, the loss of RKIP’s function in certain types of cancer cells results in epithelial to mesenchymal transition (EMT) and the promotion of cancer metastasis. In addition, RKIP inhibits autophagy by modulating LC3-lipidation and mTORC1. How the RKIP-dependent inhibition of autophagy is linked to EMT and cancer progression is still under investigation. In this study, we investigated the ways by which RKIP interacts with key gene products in EMT and autophagy during the progression of prostate cancer. We first identified the gene products of interest using the corresponding gene ontology terms. The weighted-gene co-expression network analysis (WGCNA) was applied on a gene expression dataset from three groups of prostate tissues; benign prostate hyperplasia, primary and metastatic cancer. We found two modules of highly co-expressed genes, which were preserved in other independent datasets of prostate cancer tissues. RKIP showed potentially novel interactions with one EMT and seven autophagy gene products (TGFBR1; PIK3C3, PIK3CB, TBC1D25, TBC1D5, TOLLIP, WDR45 and WIPI1). In addition, we identified several upstream transcription modulators that could regulate the expression of these gene products. Finally, we verified some RKIP novel interactions by co-localization using the confocal microscopy analysis in a prostate cancer cell line. To summarize, RKIP interacts with EMT and autophagy as part of the same functional unit in developing prostate cancer. Full article
(This article belongs to the Special Issue Targeting Raf Kinase Inhibitor Protein (RKIP) in Cancer)
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Review

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Open AccessReview Targeting Raf Kinase Inhibitory Protein Regulation and Function
Cancers 2018, 10(9), 306; https://doi.org/10.3390/cancers10090306
Received: 18 July 2018 / Revised: 24 August 2018 / Accepted: 30 August 2018 / Published: 4 September 2018
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Abstract
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Targeting Raf Kinase Inhibitor Protein (RKIP) in Cancer)
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Open AccessReview RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact
Cancers 2018, 10(9), 287; https://doi.org/10.3390/cancers10090287
Received: 20 July 2018 / Revised: 12 August 2018 / Accepted: 18 August 2018 / Published: 24 August 2018
PDF Full-text (2149 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
RAF-kinase inhibitor protein (RKIP) is a well-established tumor suppressor that is frequently downregulated in a plethora of solid and hematological malignancies. RKIP exerts antimetastatic and pro-apoptotic properties in cancer cells, via modulation of signaling pathways and gene products involved in tumor survival and
[...] Read more.
RAF-kinase inhibitor protein (RKIP) is a well-established tumor suppressor that is frequently downregulated in a plethora of solid and hematological malignancies. RKIP exerts antimetastatic and pro-apoptotic properties in cancer cells, via modulation of signaling pathways and gene products involved in tumor survival and spread. Here we review the contribution of RKIP in the regulation of early metastatic steps such as epithelial–mesenchymal transition (EMT), migration, and invasion, as well as in tumor sensitivity to conventional therapeutics and immuno-mediated cytotoxicity. We further provide updated justification for targeting RKIP as a strategy to overcome tumor chemo/immuno-resistance and suppress metastasis, through the use of agents able to modulate RKIP expression in cancer cells. Full article
(This article belongs to the Special Issue Targeting Raf Kinase Inhibitor Protein (RKIP) in Cancer)
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