STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.

Szczegóły
Abstrakt

Tytuł:: STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.
Autorzy:: Totten SP; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Im YK; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Cepeda Cañedo E; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Najyb O; Department of Biochemistry, McGill University, Montreal, QC, Canada.; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Nguyen A; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Hébert S; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Ahn R; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Lewis K; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Lebeau B; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
La Selva R; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
Sabourin V; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Martínez C; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Savage P; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Kuasne H; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Avizonis D; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Santos Martínez N; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Chabot C; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Aguilar-Mahecha A; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Goulet ML; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Dankner M; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Witcher M; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
Petrecca K; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Basik M; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
Pollak M; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
Topisirovic I; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Department of Biochemistry, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
Lin R; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Siegel PM; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Department of Biochemistry, McGill University, Montreal, QC, Canada.; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Kleinman CL; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Department Human Genetics, McGill University, Montreal, QC, Canada.
Park M; Department of Biochemistry, McGill University, Montreal, QC, Canada.; Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
St-Pierre J; Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada.
Ursini-Siegel J; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. .; Division of Experimental Medicine, McGill University, Montreal, QC, Canada. .; Department of Biochemistry, McGill University, Montreal, QC, Canada. .; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada. .
Źródło:: Nature communications [Nat Commun] 2021 Jun 03; Vol. 12 (1), pp. 3299. Date of Electronic Publication: 2021 Jun 03.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Breast Neoplasms/*drug therapy
Breast Neoplasms/*metabolism
Phenformin/*pharmacology
STAT1 Transcription Factor/*metabolism
Animals ; Antineoplastic Agents/administration & dosage ; Cell Line, Tumor ; Drug Synergism ; Electron Transport Complex I/antagonists & inhibitors ; Energy Metabolism/drug effects ; Female ; Glutathione/antagonists & inhibitors ; Glutathione/biosynthesis ; Humans ; Interferon-gamma/administration & dosage ; Interferon-gamma/deficiency ; Interferon-gamma/metabolism ; MCF-7 Cells ; Mammary Neoplasms, Experimental/drug therapy ; Mammary Neoplasms, Experimental/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mice, SCID ; NAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; Naphthoquinones/administration & dosage ; Oxidative Stress/drug effects ; Phenformin/administration & dosage ; Poly I-C/administration & dosage ; Reactive Oxygen Species/metabolism ; STAT1 Transcription Factor/agonists ; Xenograft Model Antitumor Assays
References:: Beca, F. & Polyak, K. Intratumor heterogeneity in breast cancer. Adv. Exp. Med. Biol. 882, 169–189 (2016). (PMID: 2698753510.1007/978-3-319-22909-6_7)
Kim, J. & DeBerardinis, R. J. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 30, 434–446 (2019). (PMID: 31484055673067410.1016/j.cmet.2019.08.013)
Andrzejewski, S., Gravel, S. P., Pollak, M. & St-Pierre, J. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab. 2, 12 (2014). (PMID: 25184038414738810.1186/2049-3002-2-12)
Bridges, H. R., Jones, A. J., Pollak, M. N. & Hirst, J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 462, 475–487 (2014). (PMID: 2501763010.1042/BJ20140620)
Wheaton, W. W. et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3, e02242 (2014). (PMID: 24843020401765010.7554/eLife.02242)
Pollak, M. Potential applications for biguanides in oncology. J. Clin. Invest. 123, 3693–3700 (2013). (PMID: 23999444375425010.1172/JCI67232)
Col, N. F., Ochs, L., Springmann, V., Aragaki, A. K. & Chlebowski, R. T. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res. Treat. 135, 639–646 (2012). (PMID: 2284751110.1007/s10549-012-2170-x)
Decensi, A. et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev. Res. 3, 1451–1461 (2010). (PMID: 10.1158/1940-6207.CAPR-10-0157)
Suissa, S. & Azoulay, L. Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35, 2665–2673 (2012). (PMID: 23173135350758010.2337/dc12-0788)
Pimentel, I. et al. A phase II randomized clinical trial of the effect of metformin versus placebo on progression-free survival in women with metastatic breast cancer receiving standard chemotherapy. Breast 48, 17–23 (2019). (PMID: 3147244610.1016/j.breast.2019.08.003)
Bonanni, B. et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J. Clin. Oncol. 30, 2593–2600 (2012). (PMID: 2256499310.1200/JCO.2011.39.3769)
Dowling, R. J. et al. Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res. 17, 32 (2015). (PMID: 25849721438149510.1186/s13058-015-0540-0)
Hadad, S. M. et al. Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial. Breast Cancer Res. Treat. 150, 149–155 (2015). (PMID: 2568207710.1007/s10549-015-3307-5)
Chandel, N. S. et al. Are metformin doses used in murine cancer models clinically relevant? Cell Metab. 23, 569–570 (2016). (PMID: 2707607010.1016/j.cmet.2016.03.010)
Dowling, R. J. et al. Metformin pharmacokinetics in mouse tumors: implications for human therapy. Cell Metab. 23, 567–568 (2016). (PMID: 2707606910.1016/j.cmet.2016.03.006)
Gravel, S. P. et al. Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res. 74, 7521–7533 (2014). (PMID: 2537747010.1158/0008-5472.CAN-14-2643-T)
Gui, D. Y. et al. Environment dictates dependence on mitochondrial complex I for NAD Th1 immunity with poly IC as adjuvant. J. Exp. Med. 206, 1589–1602 (2009). (PMID: 19564349271509810.1084/jem.20090247)
Listgarten, J. et al. Predictive models for breast cancer susceptibility from multiple single nucleotide polymorphisms. Clin. Cancer Res. 10, 2725–2737 (2004). (PMID: 1510267710.1158/1078-0432.CCR-1115-03)
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014). (PMID: 24695404410359010.1093/bioinformatics/btu170)
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013). (PMID: 2310488610.1093/bioinformatics/bts635)
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014). (PMID: 2422767710.1093/bioinformatics/btt656)
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). (PMID: 25516281430204910.1186/s13059-014-0550-8)
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009). (PMID: 19505943272300210.1093/bioinformatics/btp352)
Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010). (PMID: 20110278283282410.1093/bioinformatics/btq033)
Mamer, O. et al. The complete targeted profile of the organic acid intermediates of the citric acid cycle using a single stable isotope dilution analysis, sodium borodeuteride reduction and selected ion monitoring GC/MS. Metabolomics 9, 1019–1030 (2013). (PMID: 24348278385548710.1007/s11306-013-0521-1)
Mookerjee, S. A., Gerencser, A. A., Nicholls, D. G. & Brand, M. D. Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements. J. Biol. Chem. 292, 7189–7207 (2017). (PMID: 28270511540948610.1074/jbc.M116.774471)
Grant Information:: 111143 Canada CIHR; 244105 Canada CIHR
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (Naphthoquinones)
0 (Reactive Oxygen Species)
0 (STAT1 Transcription Factor)
0 (STAT1 protein, human)
6N4FA2QQ6A (beta-lapachone)
82115-62-6 (Interferon-gamma)
DD5K7529CE (Phenformin)
EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone))
EC 1.6.5.2 (NQO1 protein, human)
EC 7.1.1.2 (Electron Transport Complex I)
GAN16C9B8O (Glutathione)
O84C90HH2L (Poly I-C)
Entry Date(s):: Date Created: 20210604 Date Completed: 20210611 Latest Revision: 20221028
Update Code:: 20240104
PubMed Central ID:: PMC8175605
DOI:: 10.1038/s41467-021-23396-2
PMID:: 34083537
: Czasopismo naukowe

Full Text Finder

Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using β-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.

Informacja