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Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

  • Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

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Metadaten
Document Type:Article
Language:English
Parent Title (English):Nature Communications
Volume:9
First Page:3267
ISSN:2041-1723
URN:urn:nbn:de:hbz:1044-opus-39907
DOI:https://doi.org/10.1038/s41467-018-05763-8
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=30111846
Publisher:Nature Publishing Group
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2018/08/15
Note:
© The Author(s) 2018. This article is licensed under a Creative Commons
Attribution 4.0 International License.
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IfGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2018/08/21
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International