Targeting RPS6K1 for Refractory Breast Cancer Therapy

Sridhar, Jayalakshmi; Komati, Rajesh; Kumar, Shailendra

doi:10.36255/exon-publications-breast-cancer-rps6k1

Cited by 3 publications

(1 citation statement)

References 96 publications

(102 reference statements)

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“…Numerous studies indicate an important role of S6K1 in cancer progression. Deregulation of S6K1 signaling caused by kinase overexpression and overactivation has been found in various malignancies, including breast, lung, thyroid, brain, and esophageal cancer, which very often correlates with poor disease prognosis [8][9][10][11][12][13][14][15] and therefore makes the kinase a promising therapeutic target for cancer treatment [16].…”

Section: Introductionmentioning

confidence: 99%

Alterations in S6K1 isoforms expression induce Epithelial to Mesenchymal Transition and Estrogen Receptor 1 Silencing in human breast adenocarcinoma MCF-7 cells

Garifulin,

Zaiets,

Kosach

et al. 2023

Biopolym. Cell

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To evaluate an impact of different S6K1 isoforms expression in MCF-7 cells on initiation of Epithelial to Mesenchymal Transition (EMT). Methods. Immunocytochemical analysis, Real-Time PCR, Western blot. Results. We have demonstrated that unbalanced expression of p60, p70 and p85-S6K1 isoforms in MCF-7, namely downregulation of p70 and p85, and basal p60 expression, mediated by the CRISPR-Cas9 gene editing resulted in altered morphology and increased cell motility. Such changes were associated with the expression of genes whose products are involved in the regulation of cell motility, interaction with the extracellular matrix and loss of cellular adhesion demonstrating their increased potential for invasion and me tas tatic activity. qPCR analysis confirmed increased expression of a whole spectrum of genes associated with mesenchymal charac te ristics and loss of epithelial specific markers. Additionally, we observed a complete repression of the estrogen receptor 1 (ESR1) expression and downregulation of HER2/NEU (ERBB2). Conclusions. Our data demonstrate for the first time the implication of S6K1 isoforms in the regulation of EMT in MCF-7 cells by trigge ring for the concomitant onset of a series of possibly parallel events that changes the cell from an epithelial to a mesenchymal type and has a strong negative impact on ESR1 expression. At the tumor level that can mean breast tumor transition to a more aggressive most probably triple negative molecular subtype. K e y w o r d s: S6K1 isoforms, breast cancer, MCF-7 cells, EMT, ESR1.

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Section: Introductionmentioning

confidence: 99%

Alterations in S6K1 isoforms expression induce Epithelial to Mesenchymal Transition and Estrogen Receptor 1 Silencing in human breast adenocarcinoma MCF-7 cells

Garifulin,

Zaiets,

Kosach

et al. 2023

Biopolym. Cell

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Generation of the MCF-7 cell sublines with CRISPR/Cas9 mediated disruption of estrogen receptor alfa (ESR1) expression

Savinska,

Kvitchenko,

Palchevskyi

et al. 2024

Ukr.Biochem.J.

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Supported by the literature, our initial hypothesis was that Estrogen Receptor alfa (ESR1) may function as a master regulator by influencing the expression of epithelial-to-mesenchymal transition (EMT)-related genes in cancer cells. To explore this further, we used the CRISPR/Cas9 gene editing system to create MCF-7 sublines with down-regulated ESR1 expression and analyzed its impact on EMT initiation. By applying two distinct types of gRNA for gene editing, we established six MCF-7 cell sublines with either nearly complete or partial down-regulation of the ESR1 isoforms. Unexpectedly, the data obtained revealed no discernible impact of ESR1 down-regulation on EMT manifestation as Western blot and Real-Time qPCR analysis of selected clones revealed no changes in EMT markers expression. We suggested that those of the ESR1 isoforms, the expression of which was not affected by gene editing, could be crucial for the initiation of EMT. The obtained cell models will be used further to evaluate the activity of ESR1 isoforms. Keywords: CRISPR/Cas9, epithelial-to-mesenchymal transition, estrogen receptor alfa, MCF-7 cells

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Development of 6-amido-4-aminoisoindolyn-1,3-diones as p70S6K1 inhibitors and potential breast cancer therapeutics

Thornton,

Komati,

Kim

et al. 2024

Front. Mol. Biosci.

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IntroductionMany breast cancer therapeutics target the PI3K/AKT/mTOR oncogenic pathway. Development of resistance to the therapeutics targeting this pathway is a frequent occurrence. Therapeutics targeting p70S6K1, a downstream member of this pathway, have recently gained importance due to its critical role in all types of breast cancer and its status as a prognostic marker. We have developed a new class of p70S6K1 inhibitors that show growth inhibition of MCF7 breast cancer cells.MethodsA series of 6-amido-4-aminoisoindolyn-1,3-dione compounds was developed against p70S6K1 using docking, computational modeling tools, and synthesis of the designed compounds. The p70S6K1 inhibition potency of the compounds was investigated in an initial high-throughput screening followed by IC50 determination for the most active ones. The best compounds were subjected to proliferation assays on MCF7 breast cancer cells. The targeting of p70S6K1 by the compounds was confirmed by studying the phosphorylation status of downstream protein rpS6.ResultsIn this study, we have identified a new class of compounds as p70S6K1 inhibitors that function as growth inhibitors of MCF7 breast cancer cells. The structural features imparting p70S6K1 inhibition potency to the compounds have been mapped. Our studies indicate that substitutions on the phenacetyl group residing in the cleft A of the protein do not contribute to the inhibition potency. Three compounds (5b, 5d, and 5f) have been identified to have sub-micromolar inhibition potency for p70S6K1. These compounds also exhibited growth inhibition of MCF7 cells by 40%–60% in the presence of estradiol.

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Targeting RPS6K1 for Refractory Breast Cancer Therapy

Cited by 3 publications

References 96 publications

Alterations in S6K1 isoforms expression induce Epithelial to Mesenchymal Transition and Estrogen Receptor 1 Silencing in human breast adenocarcinoma MCF-7 cells

Alterations in S6K1 isoforms expression induce Epithelial to Mesenchymal Transition and Estrogen Receptor 1 Silencing in human breast adenocarcinoma MCF-7 cells

Generation of the MCF-7 cell sublines with CRISPR/Cas9 mediated disruption of estrogen receptor alfa (ESR1) expression

Development of 6-amido-4-aminoisoindolyn-1,3-diones as p70S6K1 inhibitors and potential breast cancer therapeutics

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