Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Nolan, Aoife A.; Aboud, Nourhan K.; Kölch, Walter; Matallanas, David

doi:10.3390/genes12040553

Cited by 17 publications

(10 citation statements)

References 83 publications

(135 reference statements)

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“…While phosphorylation and activation of MEK1/2 is the only widely accepted catalytic function of the RAF kinases, they can regulate other signalling pathways independent of their kinase activity (Rauch et al, 2011, Baccarini, 2005, Nolan et al, 2021). These include the suppression of proapoptotic pathways mediated by ASK1 (Chen et al, 2001) or MST2 (O’Neill et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

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García-Gutiérrez

Duffy

et al. 2022

Preprint

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The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with BRAFV600E mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAFi. We show that the BRAFV600E mutant protein, but not the wildtype BRAF protein, strongly binds to MST2 and inhibits MST2 pro-apoptotic signalling. Downregulation of MST2 reduces BRAFi induced apoptosis. In BRAFi resistant cell lines MST2 pathway proteins are downregulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway induced apoptosis. Restoration of apoptosis is achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway is involved in the acquisition of BRAFi resistance in melanoma.

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Section: Discussionmentioning

confidence: 99%

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

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García-Gutiérrez

Duffy

et al. 2022

Preprint

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“…RAF1 belongs to the RAF protein kinase family which contains A-RAF, B-RAF and RAF1 (C-RAF), and plays a signal conduction function in MAPK signaling pathway [ 55 ]. It has been reported in a variety of malignancies that RAF1 transmits extracellular signals into the nucleus through cell membrane receptors, thereby mediating the expression of intracellular specific proteins and participating in the regulation of cell proliferation, differentiation, apoptosis and autophagy [ 35 , 56 , 57 ]. In this study, lentivirus knockdown and overexpression of RAF1 were transfected into FADU and SCC15 cell lines, and it was proved that the downregulation of RAF1 could inhibit the proliferation, migration, invasion and promote apoptosis of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

RAF1 promotes lymphatic metastasis of hypopharyngeal carcinoma via regulating LAGE1: an experimental research

Pan

et al. 2022

J Transl Med

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Background Lymphatic metastasis was an independent prognostic risk factor for hypopharyngeal carcinoma and was the main cause of treatment failure. The purpose of this study was to screen the differential genes and investigate the mechanism of lymphatic metastasis in hypopharyngeal carcinoma. Methods Transcriptome sequencing was performed on primary tumors of patients, and differential genes were screened by bioinformatics analysis. The expression of differential genes was verified by qRT-PCR, western-blotting and immunohistochemical, and prognostic value was analyzed by Kaplan–Meier and log-rank test and Cox’s test. Next, FADU and SCC15 cell lines were used to demonstrate the function of differential genes both in vitro by EdU, Flow cytometry, Wound Healing and Transwell assays and in vivo by a foot-pad xenograft mice model. Proteomic sequencing was performed to screen relevant targets. In addition, in vitro and in vivo experiments were conducted to verify the mechanism of lymphatic metastasis. Results Results of transcriptome sequencing showed that RAF1 was a significantly differential gene in lymphatic metastasis and was an independent prognostic risk factor. In vitro experiments suggested that decreased expression of RAF1 could inhibit proliferation, migration and invasion of tumor cells and promote apoptosis. In vivo experiments indicated that RAF1 could promote tumor growth and lymphatic metastasis. Proteomic sequencing and subsequent experiments suggested that LAGE1 could promote development of tumor and lymphatic metastasis, and was regulated by RAF1. Conclusions It suggests that RAF1 can promote lymphatic metastasis of hypopharyngeal carcinoma by regulating LAGE1, and provide a basis for the exploring of novel therapeutic target and ultimately provide new guidance for the establishment of intelligent diagnosis and precise treatment of hypopharyngeal carcinoma.

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“…Interestingly, all mentioned pathways are also closely related to the regulation of mitochondrial functions. At the same time, these pathways are affected by changes in intracellular redox status driven most significantly by mitochondria [13,[38][39][40][41][42]. Thus, we focused on mitochondria and mitochondria-mediated ROS production.…”

Section: Discussionmentioning

confidence: 99%

Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells

et al. 2021

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Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of this study was to bring new insights into the mechanism behind the effects of pseurotin D on MEC-1 cells as a representative CLL cell line, with a particular focus on selected signaling pathways important in the proliferation of cells and targeting mitochondrial metabolism. Our results showed that pseurotin D was able to significantly inhibit the proliferation of MEC-1 cells and arrested them in the G2/M cell cycle phase. In addition, pseurotin D was able to induce apoptosis. We found that all of these effects were associated with a change in mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). We showed for the first time that pseurotin D suppresses MEC-1 cell proliferation and induces apoptotic cell death via induction of the collapse of the mitochondria respiratory chain and the ROS-related caspase pathway. Our results show the pseurotins family as promising compounds which could serve as a basis for the development of new compounds in the treatment of lymphoma.

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Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Cited by 17 publications

References 83 publications

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

Proteasomal downregulation of the pro-apoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma

RAF1 promotes lymphatic metastasis of hypopharyngeal carcinoma via regulating LAGE1: an experimental research

Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells

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