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• W2029376990 endingPage "e57289" @default.
• W2029376990 startingPage "e57289" @default.
• W2029376990 abstract "The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser(473) while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser(473) and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis." @default.
• W2029376990 created "2016-06-24" @default.
• W2029376990 creator A5054848065 @default.
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• W2029376990 creator A5080480389 @default.
• W2029376990 creator A5083926993 @default.
• W2029376990 date "2013-02-21" @default.
• W2029376990 modified "2023-10-17" @default.
• W2029376990 title "Different Patterns of Akt and ERK Feedback Activation in Response to Rapamycin, Active-Site mTOR Inhibitors and Metformin in Pancreatic Cancer Cells" @default.
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• W2029376990 doi "https://doi.org/10.1371/journal.pone.0057289" @default.
• W2029376990 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3578870" @default.
• W2029376990 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23437362" @default.
• W2029376990 hasPublicationYear "2013" @default.
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