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Short term starvati...
Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
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- Pateras, Ioannis S. (författare)
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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- Williams, Chloe (författare)
- Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
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- Gianniou, Despoina D. (författare)
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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- Margetis, Aggelos T. (författare)
- 2nd Department of Internal Medicine, Athens Naval and Veterans Hospital, Athens, Greece
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- Avgeris, Margaritis (författare)
- Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, “P. & A. Kyriakou” Children’s Hospital, Athens, Greece; Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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- Rousakis, Pantelis (författare)
- Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
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- Legaki, Aigli-Ioanna (författare)
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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- Mirtschink, Peter (författare)
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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- Zhang, Wei (författare)
- Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre, Umeå University, Umeå, Sweden
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- Panoutsopoulou, Konstantina (författare)
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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- Delis, Anastasios D. (författare)
- Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece
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- Pagakis, Stamatis N. (författare)
- Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece
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- Tang, Wei (författare)
- Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States; Data Science & Artificial Intelligence, R&D, AstraZeneca, MD, Gaithersburg, United States
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- Ambs, Stefan (författare)
- Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States
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- Warpman Berglund, Ulrika (författare)
- Karolinska Institutet
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- Helleday, Thomas (författare)
- Karolinska Institutet
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- Varvarigou, Anastasia (författare)
- Department of Paediatrics, University of Patras Medical School, General University Hospital, Patras, Greece
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- Chatzigeorgiou, Antonios (författare)
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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- Nordström, Anders (författare)
- Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre, Umeå University, Umeå, Sweden
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- Tsitsilonis, Ourania E. (författare)
- Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
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- Trougakos, Ioannis P. (författare)
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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- Gilthorpe, Jonathan D. (författare)
- Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)
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- Frisan, Teresa, 1967- (författare)
- Umeå universitet,Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten),Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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(creator_code:org_t)
- 2023-03-03
- 2023
- Engelska.
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Ingår i: Journal of Translational Medicine. - : BioMed Central (BMC). - 1479-5876. ; 21:1
- Relaterad länk:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Breast cancer
- Caloric restriction
- Fasting
- Metabolic reprogramming
- Mitochondria
- Oncological treatment
- Oxidative stress
- Reactive oxygen species
- Starvation
- Triple negative breast cancer
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Pateras, Ioannis ...
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Williams, Chloe
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Gianniou, Despoi ...
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Margetis, Aggelo ...
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Avgeris, Margari ...
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Rousakis, Pantel ...
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Legaki, Aigli-Io ...
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Mirtschink, Pete ...
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Zhang, Wei
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Panoutsopoulou, ...
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Delis, Anastasio ...
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Pagakis, Stamati ...
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Tang, Wei
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Ambs, Stefan
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Warpman Berglund ...
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Helleday, Thomas
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Varvarigou, Anas ...
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Chatzigeorgiou, ...
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Nordström, Ander ...
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Tsitsilonis, Our ...
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Trougakos, Ioann ...
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Gilthorpe, Jonat ...
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Frisan, Teresa, ...
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Umeå universitet
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Karolinska Institutet