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Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL

Elia, A; Henry-Grant, R; Adiseshiah, C; Marboeuf, C; Buckley, RJ; Clemens, MJ; Mudan, S; Pyronnet, S (2017) Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL. Cell Death & Disease, 8. p. 3204. ISSN 2041-4889 https://doi.org/10.1038/s41419-017-0001-z (In Press)
SGUL Authors: Elia, Androulla

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Abstract

Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1. This is associated with inhibition of mTOR activity, resulting from caspase-mediated cleavage of the Raptor and Rictor components of mTOR. Use of the pan-caspase inhibitor Z-VAD-FMK indicates that the increase in level of 4E-BP1 is also caspase-mediated. ShRNA-silencing of 4E-BP1 expression renders cells more resistant to cell death induced by the combination treatment. Since the levels of 4E-BP1 are relatively low in untreated pancreatic cancer cells these results suggest that combined therapy with gemcitabine and TRAIL could improve the responsiveness of tumours to treatment by elevating the expression of 4E-BP1.

Item Type: Article
Additional Information: © The Author(s). 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Cell Death & Disease
ISSN: 2041-4889
Dates:
DateEvent
12 December 2017Published
25 September 2017Accepted
Projects:
Project IDFunderFunder ID
UNSPECIFIEDRalph Bates Pancreatic Cancer Research FundUNSPECIFIED
UNSPECIFIEDProgramme Hospitalo-Universitaire en Cancérologie (CAPTOR)UNSPECIFIED
URI: http://openaccess.sgul.ac.uk/id/eprint/109374
Publisher's version: https://doi.org/10.1038/s41419-017-0001-z

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