40 Years of RAS—A Historic Overview

Fernández‐Medarde, Alberto; Rivas, Javier De Las; Santos, Eugenio

doi:10.3390/genes12050681

Cited by 31 publications

(21 citation statements)

References 195 publications

(222 reference statements)

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“…GEF displace guanine nucleotides from RAS and permit passive biding to GTP, which is abundant in the cytosol. On the other hand, RAS proteins are negatively regulated by GTPase-activating proteins (GAP), which markedly stimulate intrinsic GTPase activity by stabilizing a high energy-transition state that occurs during the RAS-GTP hydrolysis reaction ( Fernández-Medarde et al, 2021 ).…”

Section: Activities Of Polyphenols In Relevant Cancer-driving Signaling Pathwaysmentioning

confidence: 99%

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

2021

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Polyphenols constitute an important group of natural products that are traditionally associated with a wide range of bioactivities. These are usually found in low concentrations in natural products and are now available in nutraceuticals or dietary supplements. A group of polyphenols that include apigenin, quercetin, curcumin, resveratrol, EGCG, and kaempferol have been shown to regulate signaling pathways that are central for cancer development, progression, and metastasis. Here, we describe novel mechanistic insights on the effect of this group of polyphenols on key elements of the signaling pathways impacting cancer. We describe the protein modifications induced by these polyphenols and their effect on the central elements of several signaling pathways including PI3K, Akt, mTOR, RAS, and MAPK and particularly those affecting the tumor suppressor p53 protein. Modifications of p53 induced by these polyphenols regulate p53 gene expression and protein levels and posttranslational modifications such as phosphorylation, acetylation, and ubiquitination that influence stability, subcellular location, activation of new transcriptional targets, and the role of p53 in response to DNA damage, apoptosis control, cell- cycle regulation, senescence, and cell fate. Thus, deep understanding of the effects that polyphenols have on these key players in cancer-driving signaling pathways will certainly lead to better designed targeted therapies, with less toxicity for cancer treatment. The scope of this review centers on the regulation of key elements of cancer signaling pathways by the most studied polyphenols and highlights the importance of a profound understanding of these regulations in order to improve cancer treatment and control with natural products.

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Section: Activities Of Polyphenols In Relevant Cancer-driving Signaling Pathwaysmentioning

confidence: 99%

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

2021

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“…G proteins are defined by their ability to bind and hydrolyze the GTP molecule and can be divided in to small (or monomeric) G-proteins and heterotrimeric G-proteins. The first class is also the more numerous, since the human genome comprises 150 small GTPases belonging to the RAS superfamily [25], which have a broad localization within different intracellular organelles, and a plethora of cellular functions ranging from intracellular trafficking to regulation of signal transduction and cytoskeletal dynamics [26].…”

Section: G-protein Signaling Complexesmentioning

confidence: 99%

Endomembrane-Based Signaling by GPCRs and G-Proteins

Liccardo

Luini

Martino

2022

Cells

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G-protein-coupled receptors (GPCRs) and G-proteins have a range of roles in many physiological and pathological processes and are among the most studied signaling proteins. A plethora of extracellular stimuli can activate the GPCR and can elicit distinct intracellular responses through the activation of specific transduction pathways. For many years, biologists thought that GPCR signaling occurred entirely on the plasma membrane. However, in recent decades, many lines of evidence have proved that the GPCRs and G-proteins may reside on endomembranes and can start or propagate signaling pathways through the organelles that form the secretory route. How these alternative intracellular signaling pathways of the GPCR and G-proteins influence the physiological and pathological function of the endomembranes is still under investigation. Here, we review the general role and classification of GPCRs and G-proteins with a focus on their signaling pathways in the membrane transport apparatus.

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“…KRAS is one of the oldest and most potent oncogenes identified, along with MYC and ABL1 ( 123 , 124 ). Its role as a signaling effector downstream of MAPK signaling and in cell cycle progression has been well established across species ( 125 , 126 ).…”

Section: Future Perspectivesmentioning

confidence: 99%

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

et al. 2022

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Treatment resistance is observed in all advanced cancers. Colorectal cancer (CRC) presenting as colorectal adenocarcinoma (COAD) is the second leading cause of cancer deaths worldwide. Multimodality treatment includes surgery, chemotherapy, and targeted therapies with selective utilization of immunotherapy and radiation therapy. Despite the early success of anti-epidermal growth factor receptor (anti-EGFR) therapy, treatment resistance is common and often driven by mutations in APC, KRAS, RAF, and PI3K/mTOR and positive feedback between activated KRAS and WNT effectors. Challenges in the direct targeting of WNT regulators and KRAS have caused alternative actionable targets to gain recent attention. Utilizing an unbiased drug screen, we identified combinatorial targeting of DDR1/BCR-ABL signaling axis with small-molecule inhibitors of EGFR-ERBB2 to be potentially cytotoxic against multicellular spheroids obtained from WNT-activated and KRAS-mutant COAD lines (HCT116, DLD1, and SW480) independent of their KRAS mutation type. Based on the data-driven approach using available patient datasets (The Cancer Genome Atlas (TCGA)), we constructed transcriptomic correlations between gene DDR1, with an expression of genes for EGFR, ERBB2-4, mitogen-activated protein kinase (MAPK) pathway intermediates, BCR, and ABL and genes for cancer stem cell reactivation, cell polarity, and adhesion; we identified a positive association of DDR1 with EGFR, ERBB2, BRAF, SOX9, and VANGL2 in Pan-Cancer. The evaluation of the pathway network using the STRING database and Pathway Commons database revealed DDR1 protein to relay its signaling via adaptor proteins (SHC1, GRB2, and SOS1) and BCR axis to contribute to the KRAS-PI3K-AKT signaling cascade, which was confirmed by Western blotting. We further confirmed the cytotoxic potential of our lead combination involving EGFR/ERBB2 inhibitor (lapatinib) with DDR1/BCR-ABL inhibitor (nilotinib) in radioresistant spheroids of HCT116 (COAD) and, in an additional devastating primary cancer model, glioblastoma (GBM). GBMs overexpress DDR1 and share some common genomic features with COAD like EGFR amplification and WNT activation. Moreover, genetic alterations in genes like NF1 make GBMs have an intrinsically high KRAS activity. We show the combination of nilotinib plus lapatinib to exhibit more potent cytotoxic efficacy than either of the drugs administered alone in tumoroids of patient-derived recurrent GBMs. Collectively, our findings suggest that combinatorial targeting of DDR1/BCR-ABL with EGFR-ERBB2 signaling may offer a therapeutic strategy against stem-like KRAS-driven chemoradioresistant tumors of COAD and GBM, widening the window for its applications in mainstream cancer therapeutics.

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40 Years of RAS—A Historic Overview

Cited by 31 publications

References 195 publications

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

Endomembrane-Based Signaling by GPCRs and G-Proteins

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

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