title: Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells.
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.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ippolito
authors.affiliation: Department of Biomedical Sciences, Laboratory of Cell Signaling and Redox Biology, University of Sassari, Sassari, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Marini
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cavallini
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pietrovito
authors.affiliation: Department of Biomedical Sciences, Laboratory of Cell Signaling and Redox Biology, University of Sassari, Sassari, Italy.|Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pintus
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.affiliation: Department of Chemistry, University Duisburg-Essen, Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schrader
authors.affiliation: Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Puhr
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.|Tuscany Tumor Institute and "Center for Research, Transfer and High Education DenoTHE", Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010641:Phenotype; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D043823:Taxoids; D005973:Glutamine; D000077143:Docetaxel; D009249:NADP; D005947:Glucose
keywords: chemoresistance; docetaxel; epithelial mesenchymal transition; oxidative phosphorylation; prostate cancer