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Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells

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Title: Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells
Authors: Lam, E
Alasiri, G
Jiramongkol, Y
Zona, S
Fan, L
Mahmud, Z
Item Type: Journal Article
Abstract: The major impediment to effective cancer therapy has been the development of drug resistance. The tumour suppressive transcription factor FOXO3 promotes cell cycle arrest, senescence and cell death, and mediates the cytotoxic and cytostatic functions of cancer therapeutics. In consequence, FOXO3 is often downregulated as an adaptive response in cancer and particularly in chemotherapeutic drug-resistant cells. Consistently, we find that FOXO3 expression is attenuated in the drug-resistant MCF-7-EpiR and MCF-7-TaxR compared to the parental MCF-7 breast cancer cells. Using ChIP, short-interfering RNA (siRNA) knockdown, and overexpression assays as well as Foxo1/3/4−/− MEFs, we establish the endoplasmic reticulum (ER)-stress defence modulator PERK (eIF2AK3) as a direct downstream transcriptional target of FOXO3. In agreement, there is also a positive correlation between FOXO3 and PERK expression at the protein and RNA levels in breast cancer patient samples. We uncover that PERK expression is downregulated but its activity constitutively elevated in the drug-resistant cells. With this in mind, we exploit this adaptive response of low FOXO3 and PERK expression, and high PERK activity in drug-resistant breast cancer cells and show that these drug-resistant cells are specifically sensitive to PERK inhibition. In support of this finding, we show that ectopic overexpression of FOXO3 can reduce the sensitivity of the resistant cells to the PERK inhibitor GSK2606414, while the Foxo1/3/4−/− MEFs expressing lower levels of PERK are more sensitive to PERK inhibition compared to wild-type MEFs. PERK inhibitor-titration and -time course experiments showed that the drug-resistant cells, which express lower expression and higher activity levels of PERK, are more sensitive to the increasing concentrations of PERK inhibitor compared to parental MCF-7 cells. Our present work thus reveals a chemotherapeutic drug-resistant cancer cell vulnerability in PERK and suggests PERK as a potential target for cancer therapy, specifically in the context of drug-resistant cancers.
Issue Date: 16-Jul-2019
Date of Acceptance: 2-Jul-2019
URI: http://hdl.handle.net/10044/1/71837
DOI: 10.1038/s41388-019-0890-7
ISSN: 0950-9232
Publisher: Springer Nature
Start Page: 6382
End Page: 6398
Journal / Book Title: Oncogene
Volume: 38
Copyright Statement: © The Author(s) 2019. This article is published with 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/.
Sponsor/Funder: Cancer Research UK
Breast Cancer Care & Breast Cancer Now
Commonwealth Scholarship Commission
Royal Embassy Of Saudi Arabia
Imperial College Trust
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: 12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Online Publication Date: 2019-07-16
Appears in Collections:Department of Surgery and Cancer