We suggest targeting JAG1 may enhance therapeutic responses to mTOR inhibitors in ccRCCs.ĪLK5, Activin-like kinase 5 (TGF-β type I receptor) ANOVA, Analysis of variance Akt BEZ235 BSA, Bovine serum albumin EDTA, Ethylenediaminetetraacetic acid EMT FBS, Fetal bovine serum Hic-5 Hic-5, Hydrogen peroxide-inducible clone 5, also known as transforming growth factor beta induced transcript IRS-1, Insulin receptor substrate-1 JAG1, Jagged-1 KU-0063794 MAML-1, Mastermind-like protein-1 Myr, Myristoylated PI3K PI3K, Phosphatidylinositol 3-kinase RCC, RCC Rap, Rapamycin Rapamycin Renal cancer Rheb, Ras homologue enriched in brain SE, Standard error Slug Slug, Snail family of transcription factors encoded by the SNAI2 gene Smad, Mothers against decapentaplegic homolog Smad4 TGF-beta TGF-β, Transforming growth factor-beta TSC, Tuberous Sclerosis Complex TβRI, Transforming growth factor β receptor type 1 TβRII, Transforming growth factor β receptor type 2 ccRCC, Clear cell renal cell carcinoma mRCC, Metastatic renal cell carcinoma mTOR mTORC1, Mammalian target of rapamycin complex 1 mTORC2, Mammalian target of rapamycin complex 2. ![]() Moreover, inhibition of Notch signaling with γ-secretase inhibitors enhanced or permitted mTOR inhibitors to suppress the motility of ccRCC cells. Silencing JAG1 selectively decreased the motility of ccRCC cells treated with Rap or TGF-β1. Moreover, Rap enhanced TGF-β-induced expression of Hic-5 and Slug, both of which were repressed in JAG1-silenced ccRCC cells. Silencing JAG1 with selective shRNAs blocked the ability of KU-0063794 and Rap to induce Hic-5 in ccRCC cells. ![]() Furthermore, we show that mTOR inhibitors activate Notch1 and induce the expression of drivers of epithelial-mesenchymal transition, notably Hic-5 and Slug. Using both molecular and chemical inhibitors of PI3K, Akt, and TGF-β signaling, we provide evidence that the induction of JAG1 expression by mTOR inhibitors in ccRCC cells depends on the activation of Akt and occurs through an ALK5 kinase/Smad4-dependent mechanism. Here we provide the first report that expression of the Notch ligand Jagged-1 (JAG1), which is associated with aggressiveness of RCCs, is induced by several inhibitors of mTOR (rapamycin (Rap), BEZ235, KU-0063794) in human clear cell RCC (ccRCC) cells. Despite the notable clinical success of mTOR inhibitors in extending the overall survival of patients with certain malignancies including metastatic renal cell carcinomas (RCCs), the overall impact of mTOR inhibitors on cancers has been generally disappointing and attributed to various compensatory responses. ![]() Targeting mTOR continues to be under clinical investigation for cancer therapy. The mammalian target of rapamycin (mTOR) plays an important role in the aggressiveness and therapeutic resistance of many cancers.
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