Editorial

3 pages, 171 KiB

Open AccessEditorial

RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer

by Benjamin Bonavida

Cancers 2022, 14(24), 6092; https://doi.org/10.3390/cancers14246092 - 11 Dec 2022

Cited by 1 | Viewed by 800

Raf kinase inhibitor protein (RKIP), previously known as a phosphatidylethanolamine-binding protein (PEBP), was cloned by Yeung et al [...] Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

2 pages, 147 KiB

Open AccessEditorial

RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer

by Benjamin Bonavida

Cancers 2021, 13(10), 2488; https://doi.org/10.3390/cancers13102488 - 20 May 2021

Cited by 3 | Viewed by 1373

Abstract

Since its original cloning by Yeung et al [...] Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

Research

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12 pages, 3324 KiB

Open AccessArticle

A Negative Regulatory Role for RKIP in Breast Cancer Immune Response

by Vu N. Bach, Jane Ding, Miranda Yeung, Taylor Conrad, Hussain N. Odeh, Paige Cubberly, Christopher Figy, Han-Fei Ding, Robert Trumbly and Kam C. Yeung

Cancers 2022, 14(15), 3605; https://doi.org/10.3390/cancers14153605 - 24 Jul 2022

Cited by 2 | Viewed by 1768

Abstract

Raf-1 kinase inhibitor protein was first identified as a negative regulator of the Raf signaling pathway. Subsequently, it was shown to have a causal role in containing cancer progression and metastasis. Early studies suggested that RKIP blocks cancer progression by inhibiting the Raf-1 [...] Read more.

Raf-1 kinase inhibitor protein was first identified as a negative regulator of the Raf signaling pathway. Subsequently, it was shown to have a causal role in containing cancer progression and metastasis. Early studies suggested that RKIP blocks cancer progression by inhibiting the Raf-1 pathway. However, it is not clear if the RKIP tumor and metastasis suppression function involve other targets. In addition to the Raf signaling pathway, RKIP has been found to modulate several other signaling pathways, affecting diverse biological functions including immune response. Recent advances in medicine have identified both positive and negative roles of immune response in cancer initiation, progression and metastasis. It is possible that one way that RKIP exerts its effect on cancer is by targeting an immune response mechanism. Here, we provide evidence supporting the causal role of tumor and metastasis suppressor RKIP in downregulating signaling pathways involved with immune response in breast cancer cells and discuss its potential ramification on cancer therapy. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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19 pages, 3506 KiB

Open AccessArticle

Computational Analyses of YY1 and Its Target RKIP Reveal Their Diagnostic and Prognostic Roles in Lung Cancer

by Silvia Vivarelli, Luca Falzone, Caterina Maria Grillo, Benjamin Bonavida, Claudia Crimi, Ignazio La Mantia and Massimo Libra

Cancers 2022, 14(4), 922; https://doi.org/10.3390/cancers14040922 - 12 Feb 2022

Cited by 5 | Viewed by 1870

Abstract

Lung cancer (LC) represents a global threat, being the tumor with the highest mortality rate. Despite the introduction of novel therapies (e.g., targeted inhibitors, immune-checkpoint inhibitors), relapses are still very frequent. Accordingly, there is an urgent need for reliable predictive biomarkers and therapeutically [...] Read more.

Lung cancer (LC) represents a global threat, being the tumor with the highest mortality rate. Despite the introduction of novel therapies (e.g., targeted inhibitors, immune-checkpoint inhibitors), relapses are still very frequent. Accordingly, there is an urgent need for reliable predictive biomarkers and therapeutically druggable targets. Yin-Yang 1 (YY1) is a transcription factor that may work either as an oncogene or a tumor suppressor, depending on the genotype and the phenotype of the tumor. The Raf Kinase Inhibitory Protein (RKIP), is a tumor suppressor and immune enhancer often found downregulated in the majority of the examined cancers. In the present report, the role of both YY1 and RKIP in LC is thoroughly explored through the analysis of several deposited RNA and protein expression datasets. The computational analyses revealed that YY1 negatively regulates RKIP expression in LC, as corroborated by the deposited YY1-ChIP-Seq experiments and validated by their robust negative correlation. Additionally, YY1 expression is significantly higher in LC samples compared to normal matching ones, whereas RKIP expression is lower in LC and high in normal matching tissues. These observed differences, unlike many current biomarkers, bear a diagnostic significance, as proven by the ROC analyses. Finally, the survival data support the notion that both YY1 and RKIP might represent strong prognostic biomarkers. Overall, the reported findings indicate that YY1 and RKIP expression levels may play a role in LC as potential biomarkers and therapeutic targets. However, further studies will be necessary to validate the in silico results. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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29 pages, 1601 KiB

Open AccessArticle

A Stochastic Binary Model for the Regulation of Gene Expression to Investigate Responses to Gene Therapy

by Guilherme Giovanini, Luciana R. C. Barros, Leonardo R. Gama, Tharcisio C. Tortelli, Jr. and Alexandre F. Ramos

Cancers 2022, 14(3), 633; https://doi.org/10.3390/cancers14030633 - 27 Jan 2022

Cited by 3 | Viewed by 2747

Abstract

In this manuscript, we use an exactly solvable stochastic binary model for the regulation of gene expression to analyze the dynamics of response to a treatment aiming to modulate the number of transcripts of a master regulatory switching gene. The challenge is to [...] Read more.

In this manuscript, we use an exactly solvable stochastic binary model for the regulation of gene expression to analyze the dynamics of response to a treatment aiming to modulate the number of transcripts of a master regulatory switching gene. The challenge is to combine multiple processes with different time scales to control the treatment response by a switching gene in an unavoidable noisy environment. To establish biologically relevant timescales for the parameters of the model, we select the RKIP gene and two non-specific drugs already known for changing RKIP levels in cancer cells. We demonstrate the usefulness of our method simulating three treatment scenarios aiming to reestablish RKIP gene expression dynamics toward a pre-cancerous state: (1) to increase the promoter’s ON state duration; (2) to increase the mRNAs’ synthesis rate; and (3) to increase both rates. We show that the pre-treatment kinetic rates of ON and OFF promoter switching speeds and mRNA synthesis and degradation will affect the heterogeneity and time for treatment response. Hence, we present a strategy for reaching increased average mRNA levels with diminished heterogeneity while reducing drug dosage by simultaneously targeting multiple kinetic rates that effectively represent the chemical processes underlying the regulation of gene expression. The decrease in heterogeneity of treatment response by a target gene helps to lower the chances of emergence of resistance. Our approach may be useful for inferring kinetic constants related to the expression of antimetastatic genes or oncogenes and for the design of multi-drug therapeutic strategies targeting the processes underpinning the expression of master regulatory genes. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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20 pages, 1973 KiB

Open AccessArticle

A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells

by Mahmoud Ahmed, Trang Huyen Lai, Wanil Kim and Deok Ryong Kim

Cancers 2021, 13(23), 6098; https://doi.org/10.3390/cancers13236098 - 03 Dec 2021

Cited by 7 | Viewed by 2091

Abstract

Drug screening strategies focus on quantifying the phenotypic effects of different compounds on biological systems. High-throughput technologies have the potential to understand further the mechanisms by which these drugs produce the desired outcome. Reverse causal reasoning integrates existing biological knowledge and measurements of [...] Read more.

Drug screening strategies focus on quantifying the phenotypic effects of different compounds on biological systems. High-throughput technologies have the potential to understand further the mechanisms by which these drugs produce the desired outcome. Reverse causal reasoning integrates existing biological knowledge and measurements of gene and protein abundances to infer their function. This approach can be employed to appraise the existing biological knowledge and data to prioritize targets for cancer therapies. We applied text mining and a manual literature search to extract known interactions between several metastasis suppressors and their regulators. We then identified the relevant interactions in the breast cancer cell line MCF7 using a knockdown dataset. We finally adopted a reverse causal reasoning approach to evaluate and prioritize pathways that are most consistent and responsive to drugs that inhibit cell growth. We evaluated this model in terms of agreement with the observations under treatment of several drugs that produced growth inhibition of cancer cell lines. In particular, we suggested that the metastasis suppressor PEBP1/RKIP is on the receiving end of two significant regulatory mechanisms. One involves RELA (transcription factor p65) and SNAI1, which were previously reported to inhibit PEBP1. The other involves the estrogen receptor (ESR1), which induces PEBP1 through the kinase NME1. Our model was derived in the specific context of breast cancer, but the observed responses to drug treatments were consistent in other cell lines. We further validated some of the predicted regulatory links in the breast cancer cell line MCF7 experimentally and highlighted the points of uncertainty in our model. To summarize, our model was consistent with the observed changes in activity with drug perturbations. In particular, two pathways, including PEBP1, were highly responsive and would be likely targets for intervention. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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Review

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14 pages, 971 KiB

Open AccessReview

Understanding Mechanisms of RKIP Regulation to Improve the Development of New Diagnostic Tools

by Massimo Papale, Giuseppe Stefano Netti, Giovanni Stallone and Elena Ranieri

Cancers 2022, 14(20), 5070; https://doi.org/10.3390/cancers14205070 - 17 Oct 2022

Cited by 3 | Viewed by 1745

Abstract

One of the most dangerous aspects of cancer cell biology is their ability to grow, spread and form metastases in the main vital organs. The identification of dysregulated markers that drive intracellular signalling involved in the malignant transformation of neoplastic cells and the [...] Read more.

One of the most dangerous aspects of cancer cell biology is their ability to grow, spread and form metastases in the main vital organs. The identification of dysregulated markers that drive intracellular signalling involved in the malignant transformation of neoplastic cells and the understanding of the mechanisms that regulate these processes is undoubtedly a key objective for the development of new and more targeted therapies. RAF-kinase inhibitor protein (RKIP) is an endogenous tumour suppressor protein that affects tumour cell survival, proliferation, and metastasis. RKIP might serve as an early tumour biomarker since it exhibits significantly different expression levels in various cancer histologies and it is often lost during metastatic progression. In this review, we discuss the specific impact of transcriptional, post-transcriptional and post-translational regulation of expression and activation/inhibition of RKIP and focus on those tumours for which experimental data on all these factors are available. In this way, we could select how these processes cooperate with RKIP expression in (1) Lung cancer; (2) Colon cancer, (3) Breast cancer; (4) myeloid neoplasm and Multiple Myeloma, (5) Melanoma and (6) clear cell Renal Cell Carcinoma. Furthermore, since RKIP seems to be a key marker of the development of several tumours and it may be assessed easily in various biological fluids, here we discuss the potential role of RKIP dosing in more accessible biological matrices other than tissues. Moreover, this objective may intercept the still unmet need to identify new and more accurate markers for the early diagnosis and prognosis of many tumours. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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13 pages, 777 KiB

Open AccessReview

Harnessing RKIP to Combat Heart Disease and Cancer

by Kristina Lorenz and Marsha Rich Rosner

Cancers 2022, 14(4), 867; https://doi.org/10.3390/cancers14040867 - 09 Feb 2022

Cited by 3 | Viewed by 1794

Abstract

Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators [...] Read more.

Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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19 pages, 2035 KiB

Open AccessReview

Insights of RKIP-Derived Suppression of Prostate Cancer

by Ying Dong, Xiaozeng Lin, Anil Kapoor, Yan Gu, Hui Xu, Pierre Major and Damu Tang

Cancers 2021, 13(24), 6388; https://doi.org/10.3390/cancers13246388 - 20 Dec 2021

Cited by 5 | Viewed by 3163

Abstract

Prostate cancer (PC) is a major cause of cancer death in men. The disease has a great disparity in prognosis. Although low grade PCs with Gleason scores ≤ 6 are indolent, high-risk PCs are likely to relapse and metastasize. The standard of care [...] Read more.

Prostate cancer (PC) is a major cause of cancer death in men. The disease has a great disparity in prognosis. Although low grade PCs with Gleason scores ≤ 6 are indolent, high-risk PCs are likely to relapse and metastasize. The standard of care for metastatic PC (mPC) remains androgen deprivation therapy (ADT). Resistance commonly occurs in the form of castration resistant PC (CRPC). Despite decades of research efforts, CRPC remains lethal. Understanding of mechanisms underpinning metastatic progression represents the overarching challenge in PC research. This progression is regulated by complex mechanisms, including those regulating PC cell proliferation, epithelial–mesenchymal transition (EMT), and androgen receptor (AR) signaling. Among this PC metastatic network lies an intriguing suppressor of PC metastasis: the Raf kinase inhibitory protein (RKIP). Clinically, the RKIP protein is downregulated in PC, and showed further reduction in mPC. In xenograft mouse models for PC, RKIP inhibits metastasis. In vitro, RKIP reduces PC cell invasion and sensitizes PC cells to therapeutic treatments. Mechanistically, RKIP suppresses Raf-MEK-ERK activation and EMT, and modulates extracellular matrix. In return, Snail, NFκB, and the polycomb protein EZH2 contribute to inhibition of RKIP expression. In this review, we will thoroughly analyze RKIP’s tumor suppression actions in PC. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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38 pages, 4834 KiB

Open AccessReview

RKIP Pleiotropic Activities in Cancer and Inflammatory Diseases: Role in Immunity

by Roni Touboul, Stavroula Baritaki, Apostolos Zaravinos and Benjamin Bonavida

Cancers 2021, 13(24), 6247; https://doi.org/10.3390/cancers13246247 - 13 Dec 2021

Cited by 5 | Viewed by 4121

Abstract

Several gene products play pivotal roles in the induction of inflammation and the progression of cancer. The Raf kinase inhibitory protein (RKIP) is a cytosolic protein that exerts pleiotropic activities in such conditions, and thus regulates oncogenesis and immune-mediated diseases through its deregulation. [...] Read more.

Several gene products play pivotal roles in the induction of inflammation and the progression of cancer. The Raf kinase inhibitory protein (RKIP) is a cytosolic protein that exerts pleiotropic activities in such conditions, and thus regulates oncogenesis and immune-mediated diseases through its deregulation. Herein, we review the general properties of RKIP, including its: (i) molecular structure; (ii) involvement in various cell signaling pathways (i.e., inhibition of the Raf/MEK/ERK pathway; the NF-kB pathway; GRK-2 or the STAT-3 pathway; as well as regulation of the GSK3Beta signaling; and the spindle checkpoints); (iii) regulation of RKIP expression; (iv) expression’s effects on oncogenesis; (v) role in the regulation of the immune system to diseases (i.e., RKIP regulation of T cell functions; the secretion of cytokines and immune mediators, apoptosis, immune check point inhibitors and RKIP involvement in inflammatory diseases); and (vi) bioinformatic analysis between normal and malignant tissues, as well as across various immune-related cells. Overall, the regulation of RKIP in different cancers and inflammatory diseases suggest that it can be used as a potential therapeutic target in the treatment of these diseases. Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

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