Ras Signaling in Breast Cancer

Moon, Aree

doi:10.1007/978-981-32-9620-6_4

Cited by 12 publications

(8 citation statements)

References 143 publications

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“…Furthermore, Ras proteins activate the cytoplasm and extracellular signaling networks via receptor tyrosine kinase and are involved in cell proliferation, survival, growth, metabolism, motility, and apoptosis, and their hyperactivation promotes the growth and progression of breast cancer. In addition, Ras’s intracellular localization, activation, and signaling have been used in developing therapeutic candidates against breast cancer via the enzymes involved in posttranslational modification of Ras e.g., farnesyltransferase and geranylgeranyltransferase 1 ( Moon, 2021 ). Further, MAPK links the extracellular mitogenic signals to cell proliferation which may be concerned with or act independently towards estrogen-mediated events in breast cancer cells ( Yue et al, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Systems and in vitro pharmacology profiling of diosgenin against breast cancer

Khanal

Patil²,

Bhandare

et al. 2023

Front. Pharmacol.

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Aim: The purpose of this study was to establish a mode of action for diosgenin against breast cancer employing a range of system biology tools and to corroborate its results with experimental facts.Methodology: The diosgenin-regulated domains implicated in breast cancer were enriched in the Kyoto Encyclopedia of Genes and Genomes database to establish diosgenin-protein(s)-pathway(s) associations. Later, molecular docking and the lead complexes were considered for molecular dynamics simulations, MMPBSA, principal component, and dynamics cross-correlation matrix analysis using GROMACS v2021. Furthermore, survival analysis was carried out for the diosgenin-regulated proteins that were anticipated to be involved in breast cancer. For gene expression analyses, the top three targets with the highest binding affinity for diosgenin and tumor expression were examined. Furthermore, the effect of diosgenin on cell proliferation, cytotoxicity, and the partial Warburg effect was tested to validate the computational findings using functional outputs of the lead targets.Results: The protein-protein interaction had 57 edges, an average node degree of 5.43, and a p-value of 3.83e-14. Furthermore, enrichment analysis showed 36 KEGG pathways, 12 cellular components, 27 molecular functions, and 307 biological processes. In network analysis, three hub proteins were notably modulated: IGF1R, MDM2, and SRC, diosgenin with the highest binding affinity with IGF1R (binding energy −8.6 kcal/mol). Furthermore, during the 150 ns molecular dynamics (MD) projection run, diosgenin exhibited robust intermolecular interactions and had the least free binding energy with IGF1R (−35.143 kcal/mol) compared to MDM2 (−34.619 kcal/mol), and SRC (-17.944 kcal/mol). Diosgenin exhibited the highest cytotoxicity against MCF7 cell lines (IC50 12.05 ± 1.33) µg/ml. Furthermore, in H2O2-induced oxidative stress, the inhibitory constant (IC50 7.68 ± 0.51) µg/ml of diosgenin was lowest in MCF7 cell lines. However, the reversal of the Warburg effect by diosgenin seemed to be maximum in non-cancer Vero cell lines (EC50 15.27 ± 0.95) µg/ml compared to the rest. Furthermore, diosgenin inhibited cell proliferation in SKBR3 cell lines more though.Conclusion: The current study demonstrated that diosgenin impacts a series of signaling pathways, involved in the advancement of breast cancer, including FoxO, PI3K-Akt, p53, Ras, and MAPK signaling. Additionally, diosgenin established a persistent diosgenin-protein complex and had a significant binding affinity towards IGF1R, MDM2, and SRC. It is possible that this slowed down cell growth, countered the Warburg phenomenon, and showed the cytotoxicity towards breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Systems and in vitro pharmacology profiling of diosgenin against breast cancer

Khanal

Patil²,

Bhandare

et al. 2023

Front. Pharmacol.

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“…Ras is an oncogene whose hyperactivation plays an important role in BC growth and progression, whose effective control is one of the strategies in the treatment of BC 38 . The Ras signaling pathway is involved in cell proliferation and growth, cell survival and apoptosis in BC progression 39 ; 40 .…”

Section: Discussionmentioning

confidence: 99%

The Inhibitory Effect of Resina draconis on the Proliferation of MCF-7 Breast Cancer Cells, and its Mechanism: An Investigation Using Network Pharmacology-Based Analysis

Mou

et al. 2022

Preprint

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Resina draconis(RD), is known as the "holy medicine for promoting blood circulation", which is shown to possess anti-tumor properties in various types of cancer include Breast cancer(BC), however, the underlying mechanism is not well understood. To explore the potential mechanism of RD against BC using network pharmacology and experimental validation. Data on bioactive compounds, potential targets of RD, related genes of BC, were obtained from multiple public databases. Gene ontology (GO) and KEGG pathway analysis were performed via the DAVID database. The protein interaction was download from STRING database. The mRNA, protein expression levels and survival analysis of the hub targets were analyzed using UALCAN, HPA, Kaplan-Meier Mapper, and cBioPortal databases. Subsequently, molecular docking was used to verify the selected key ingredients and hub targets. Finally, the predicted results of network pharmacology methods were verified by cells experiments. In total, 160 active ingredients were obtained, 148 RD target genes for the treatment of BC were identified. KEGG pathway analysis indicated that RD could exert its therapeutic effects on BC by regulating multiple pathways. Of these, the PI3K-AKT pathway could play an important role. In addition, RD could treat BC by regulating hub targets that were determined with the PPI interaction network. The validation in different databases showed that may AKT1, ESR1, HSP90AA1, CASP3, SRC and MDM2 be involved in the carcinogenesis and progression of BC, as well as ESR1, IGF1 and HSP90AA1 were correlated to worse overall survival (OS) in BC. Molecular docking results showed that flavonoids compounds have good binding activity with the hub targets. Therefore, the sanguis draconis flavones (SDF) were selected for subsequent cell experiments. The experimental results showed that SDF significantly inhibits the cell cycle and cell proliferation through the PI3K-AKT pathway and that it can induce apoptosis of MCF-7 cells. The study has preliminarily discussed the active ingredients, potential targets, and molecular mechanism of RD against BC; and RD could exert its therapeutic effects on BC by regulating PI3K/AKT pathway and related gene targets. Importantly, our work could provide a theoretical basis for further study on its complex anti-BC mechanism.

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“…In the MCF-7 untreated cells, oncogenic RAS-induced proliferative signals resulted in the upregulation of transcriptional factors required for cell cycle entrance and cellular progression. Additionally, the metabolic stability of cyclin D1 was affected by the suppression of glycogen synthase kinase (GSK) 3β, which is correlated with continuous ubiquitination and proteasomal degradation of cyclin D1 via PI3K-dependent phosphorylation 17 . Moreover, oncogenic RAS accelerates cell cycle progression by reducing the inhibition caused by antigrowth signaling pathways which inhibit cyclin-dependent kinase (CDK) inhibitors like p21 42 .…”

Section: Induction Of Cell Cycle Arrest Of the Mcf-7 Cells By Compoun...mentioning

confidence: 99%

“…RAS proteins transmit extracellular signals to the cytoplasmic signaling network via tyrosine kinase receptors then to the nucleus which in turn promotes the transcription of genes involved in cell growth, proliferation, and death. The hyperactive RAS signaling contributes significantly to breast cancer's growth, progression, and metastasis which is also linked to breast cancer patients' lower survival rates 17 . Thus, the effective control of oncogenic RAS is a therapeutic strategy in breast cancer 18 .…”

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confidence: 99%

Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells

Salem

Gerges

Noser

2022

Sci Rep

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In the present investigation, derivatives from (2–6) containing pyrimidine-2-thione moiety incorporated with different heterocycles such as pyrazoline, phenyl pyrazoline, and pyrimidine were synthesized using different methods. These pyrimidine-2-thione derivatives were evaluated in-silico for their capability to inhibit the H-RAS-GTP active form protein with insight to their pharmacokinetics properties. According to our findings, compound 5a was selected for in vitro studies as it has the in-silico top-ranked binding energy. Furthermore, compound 5a induced apoptosis to panels of cancer cell lines with the best IC50 on MCF-7 breast cancer cells (2.617 ± 1.6 µM). This effect was associated with the inhibition of phosphorylated RAS, JNK proteins, and PI3K/Akt genes expression. Thus, compound 5a has upregulated p21 gene and p53 protein levels. Moreover, 5a arrested the cell cycle progression at the sub-G0/G1 phase. In conclusion, the synthesized compound, 5a exhibited potent antineoplastic activity against breast cancer cell growth by targeting RAS/ PI3K/Akt/ JNK signaling cascades.

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Ras Signaling in Breast Cancer

Cited by 12 publications

References 143 publications

Systems and in vitro pharmacology profiling of diosgenin against breast cancer

Systems and in vitro pharmacology profiling of diosgenin against breast cancer

The Inhibitory Effect of Resina draconis on the Proliferation of MCF-7 Breast Cancer Cells, and its Mechanism: An Investigation Using Network Pharmacology-Based Analysis

Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells

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