Targeting Raf Kinase Inhibitory Protein Regulation and Function

Yesilkanal, Ali E.; Rosner, Marsha Rich

doi:10.3390/cancers10090306

Cited by 42 publications

(64 citation statements)

References 71 publications

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“…RKIP inhibits the activity of Raf and other kinases in cultured cells (reviewed in 27 ). To identify kinases targeted by RKIP in TNBC tumors, we analyzed changes in kinase expression and activity by MIB-MS analysis 3 .…”

Section: Rkip Targets Multiple Kinases In the Stress Mapk Networkmentioning

confidence: 99%

“…Interestingly, several of these metastasis suppressors are kinases or proteins that modify signaling cascades and provide insight into metastatic signaling mechanisms. One of these, Raf Kinase Inhibitory Protein (RKIP; PEBP1), is a regulator of Raf kinase activity that is deleted or lost in virtually all metastatic solid tumors (reviewed by Yesilkanal and Rosner, 2018). Reintroducing RKIP to metastatic TNBC cells blocks invasion of cells in vitro and inhibits intravasation and metastasis of tumor cells in vivo 9 .…”

mentioning

confidence: 99%

“…Data already available from MEK inhibitor Phase 1 trials 46 should enable an estimate of drug doses that would reduce MEK activity by less than 30%, and similar analyses can be carried out for the other kinase inhibitors. Effective treatment based on inducing functional RKIP in tumors has not been possible since RKIP regulation is complex and occurs at multiple levels including transcriptional, translational and post-translational(Yesilkanal and Rosner, 2018). By significantly expanding our knowledge of RKIP function as a tumor metastasis suppressor, this study identifies additional therapeutic targets.…”

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confidence: 99%

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Limited inhibition of multiple nodes in a driver network blocks metastasis

Yesilkanal

Yang

Tiwari

et al. 2020

Preprint

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Metastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of its core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stressregulated MAP kinase network activity, reducing the output to metastatic transcription factor BACH1 and motilityrelated target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show: 1) limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells, and 2) restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for antimetastatic treatment.

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Section: Rkip Targets Multiple Kinases In the Stress Mapk Networkmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Limited inhibition of multiple nodes in a driver network blocks metastasis

Yesilkanal

Yang

Tiwari

et al. 2020

Preprint

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“…This multifunctional capacity of RKIP is associated with its involvement in the modulation of several signalling pathways (Reviewed at [4][5][6][7][8]). This protein was first described as a regulator of the Raf-MEK-ERK pathway, acting as its endogenous inhibitor.…”

Section: Introductionmentioning

confidence: 99%

“…Due to its important role as a modulator of intracellular signalling pathways that control several cellular processes, the deregulated expression of RKIP is implicated in several pathologies, including cancer [4,6]. The first association between RKIP and cancer was established in prostate metastatic cell lines, in which cellular RKIP expression levels were lower when compared to primary tumour cell lines [15].…”

Section: Introductionmentioning

confidence: 99%

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

et al. 2019

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Raf kinase inhibitor protein (RKIP), an important modulator of intracellular signalling pathways, is commonly downregulated in multiple cancers. This reduction, or loss of expression, is correlated not only with the presence of metastasis, contributing to RKIP’s classification as a metastasis suppressor, but also with tumour aggressiveness and poor prognosis. Recent findings suggest a strong involvement of RKIP in the modulation of tumour microenvironment components, particularly by controlling the infiltration of specific immune cells and secretion of pro-metastatic factors. Additionally, RKIP interaction with multiple signalling molecules seems to potentiate its function as a regulator of inflammatory processes, mainly through stimulation of anti- or pro-inflammatory cytokines. Furthermore, RKIP is involved in the modulation of immunotherapeutic drugs response, through diverse mechanisms that sensitize cells to apoptosis. In the present review, we will provide updated information about the role of RKIP as an inflammatory and immune modulator and its potential implications in cancer will be addressed.

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MEK inhibitors and DA‐Raf, a dominant‐negative antagonist of the Ras–ERK pathway, prevent the migration and invasion of KRAS‐mutant cancer cells

Matsuda,

Masuzawa,

Takahashi

et al. 2024

Cytoskeleton

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The Ras‐induced ERK pathway (Raf–MEK–ERK signaling cascade) regulates a variety of cellular responses including cell proliferation, survival, and migration. Activating mutations in RAS genes, particularly in the KRAS gene, constitutively activate the ERK pathway, resulting in tumorigenesis, cancer cell invasion, and metastasis. DA‐Raf1 (DA‐Raf) is a splicing isoform of A‐Raf and contains the Ras‐binding domain but lacks the kinase domain. Consequently, DA‐Raf antagonizes the Ras–ERK pathway in a dominant‐negative manner and can serve as a tumor suppressor that targets mutant Ras protein‐induced tumorigenesis. We show here that MEK inhibitors and DA‐Raf interfere with the in vitro collective cell migration and invasion of human KRAS‐mutant carcinoma cell lines, the lung adenocarcinoma A549, colorectal carcinoma HCT116, and pancreatic carcinoma MIA PaCa‐2 cells. DA‐Raf expression was silenced in these cancer cell lines. All these cell lines had high collective migration abilities and invasion properties in Matrigel, compared with nontumor cells. Their migration and invasion abilities were impaired by suppressing the ERK pathway with the MEK inhibitors U0126 and trametinib, an approved anticancer drug. Expression of DA‐Raf in MIA PaCa‐2 cells reduced the ERK activity and hindered the migration and invasion abilities. Therefore, DA‐Raf may function as an invasion suppressor protein in the KRAS‐mutant cancer cells by blocking the Ras–ERK pathway when DA‐Raf expression is induced in invasive cancer cells.

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Targeting Raf Kinase Inhibitory Protein Regulation and Function

Cited by 42 publications

References 71 publications

Limited inhibition of multiple nodes in a driver network blocks metastasis

Limited inhibition of multiple nodes in a driver network blocks metastasis

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

MEK inhibitors and DA‐Raf, a dominant‐negative antagonist of the Ras–ERK pathway, prevent the migration and invasion of KRAS‐mutant cancer cells

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