Author:
Pateras Ioannis S.,Williams Chloe,Gianniou Despoina D.,Margetis Aggelos T.,Avgeris Margaritis,Rousakis Pantelis,Legaki Aigli-Ioanna,Mirtschink Peter,Zhang Wei,Panoutsopoulou Konstantina,Delis Anastasios D.,Pagakis Stamatis N.,Tang Wei,Ambs Stefan,Warpman Berglund Ulrika,Helleday Thomas,Varvarigou Anastasia,Chatzigeorgiou Antonios,Nordström Anders,Tsitsilonis Ourania E.,Trougakos Ioannis P.,Gilthorpe Jonathan D.,Frisan Teresa
Abstract
Abstract
Background
Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.
Methods
The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.
Results
We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.
Conclusions
Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.
Funder
Hellenic GSRT
Cancer Research Foundation in Northern Sweden
Swedish Research Council
Kempestiftelserna
Swedish Cancer Society
ALF-investment award for medical and technical equipment
Umea University
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
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