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Title: Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition.
Austin Authors: Raninga, Prahlad V;Lee, Andy;Sinha, Debottam;Dong, Lan-Feng;Datta, Keshava K;Lu, Xue;Kalita-de Croft, Priyakshi;Dutt, Mriga;Hill, Michelle;Pouliot, Normand;Gowda, Harsha;Kalimutho, Murugan;Neuzil, Jiri;Khanna, Kum Kum
Affiliation: QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane QLD 4006, Australia
Radiation Biology Research Center, Institute for Radiological Research, Chang Gung Memorial Hospital/Chang Gung University, Taoyuan 333, Taiwan
Institute of Biotechnology, Czech Academy of Sciences, Prague-West, 252 50 Czech Republic
School of Medical Science, Griffith University, Southport, QLD 4222, Australia
UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Herston, QLD 4029, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: 6-Apr-2020 2020-04-06
Publication information: Theranostics 2020; 10(12): 5259-5275
Abstract: Purpose: Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive and metastatic disease, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Hence, developing effective targeted therapy using potent proteasome inhibitor is required. Methods: We evaluated anti-cancer activity of a potent proteasome inhibitor, marizomib, in vitro using breast cancer lines and in vivo using 4T1.2 murine syngeneic model, MDA-MB-231 xenografts, and patient-derived tumor xenografts. Global proteome profiling, western blots, and RT-qPCR were used to investigate the mechanism of action for marizomib. Effect of marizomib on lung and brain metastasis was evaluated using syngeneic 4T1BR4 murine TNBC model in vivo. Results: We show that marizomib inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, we show that marizomib is a dual inhibitor of proteasome and oxidative phosphorylation (OXPHOS) in TNBCs. Marizomib reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of genes involved in the epithelial-to-mesenchymal transition. We demonstrate that marizomib-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and combined inhibition of glycolysis with marizomib leads to a synergistic anti-cancer activity. Conclusions: Our data provide a strong rationale for a clinical evaluation of marizomib in primary and metastatic TNBC patients.
DOI: 10.7150/thno.42705
PubMed URL: 32373211
Type: Journal Article
Subjects: Marizomib
oxidative phosphorylation
triple-negative breast cancer
Appears in Collections:Journal articles

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