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Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells

2016; Impact Journals LLC; Volume: 7; Issue: 38 Linguagem: Inglês

10.18632/oncotarget.11301

1949-2553

Luigi Ippolito, Alberto Marini, Lorenzo Cavallini, Andrea Morandi, Laura Pietrovito, Gianfranco Pintus, Elisa Giannoni, Thomas Schräder, Martin Puhr, Paola Chiarugi, Maria Letizia Taddei,

Cancer, Lipids, and Metabolism

// Luigi Ippolito 1 , Alberto Marini 5 , Lorenzo Cavallini 1 , Andrea Morandi 1 , Laura Pietrovito 1 , Gianfranco Pintus 5, 6 , Elisa Giannoni 1 , Thomas Schrader 2 , Martin Puhr 3 , Paola Chiarugi 1, 4, * , Maria Letizia Taddei 7, * 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy 2 Department of Chemistry, University Duisburg-Essen, Essen, Germany 3 Department of Urology, Medical University of Innsbruck, Innsbruck, Austria 4 Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”, Florence, Italy 5 Department of Biomedical Sciences, Laboratory of Cell Signaling and Redox Biology, University of Sassari, Sassari, Italy 6 Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar 7 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy * These authors have contributed equally to this work Correspondence to: Maria Letizia Taddei, email: marialetizia.taddei@unifi.it Keywords: prostate cancer, chemoresistance, docetaxel, oxidative phosphorylation, epithelial mesenchymal transition Received: March 30, 2016 Accepted: July 27, 2016 Published: August 16, 2016 ABSTRACT Drug resistance of cancer cells is recognized as the primary cause of failure of chemotherapeutic treatment in most human cancers. Growing evidences support the idea that deregulated cellular metabolism is linked to such resistance. Indeed, both components of the glycolytic and mitochondrial pathways are involved in altered metabolism linked to chemoresistance of several cancers. Here we investigated the drug-induced metabolic adaptations able to confer advantages to docetaxel resistant prostate cancer (PCa) cells. We found that docetaxel-resistant PC3 cells (PC3-DR) acquire a pro-invasive behavior undergoing epithelial-to-mesenchymal-transition (EMT) and a decrease of both intracellular ROS and cell growth. Metabolic analyses revealed that PC3-DR cells have a more efficient respiratory phenotype than sensitive cells, involving utilization of glucose, glutamine and lactate by the mitochondrial oxidative phosphorylation (OXPHOS). Consequently, targeting mitochondrial complex I by metformin administration, impairs proliferation and invasiveness of PC3-DR cells without effects on parental cells. Furthermore, stromal fibroblasts, which cause a “reverse Warburg” phenotype in PCa cells, reduce docetaxel toxicity in both sensitive and resistant PCa cells. However, re-expression of miR-205, a microRNA strongly down-regulated in EMT and associated to docetaxel resistance, is able to shift OXPHOS to a Warburg metabolism, thereby resulting in an elevated docetaxel toxicity in PCa cells. Taken together, these findings suggest that resistance to docetaxel induces a shift from Warburg to OXPHOS, mandatory for conferring a survival advantage to resistant cells, suggesting that impairing such metabolic reprogramming could be a successful therapeutic approach.