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AuthorIppolito, Luigi
AuthorMarini, Alberto
AuthorCavallini, Lorenzo
AuthorMorandi, Andrea
AuthorPietrovito, Laura
AuthorPintus, Gianfranco
AuthorGiannoni, Elisa
AuthorSchrader, Thomas
AuthorPuhr, Martin
AuthorChiarugi, Paola
AuthorTaddei, Maria Letizia
Available date2016-10-16T09:21:40Z
Publication Date2016-08-16
Publication NameOncotargeten_US
Identifierhttp://dx.doi.org/10.18632/oncotarget.11301
CitationIppolito, L., Marini, A., Cavallini, L., Morandi, A., Pietrovito, L., Pintus, G., Giannoni, E., Schrader, T., Puhr, M., Chiarugi, P., & Letizia Taddei, M. (2016). Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells. Oncotarget, 7(38), 61890-61904.
URIhttp://hdl.handle.net/10576/4888
AbstractDrug 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.
SponsorAssociazione Italiana Ricerca sul Cancro (AIRC), Istituto Toscano Tumori and Regione Toscana
Languageen
PublisherImpact Journals
Subjectprostate cancer
Subjectchemoresistance
Subjectdocetaxel
Subjectoxidative phosphorylation
Subjectepithelial mesenchymal transition
TitleMetabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells
TypeArticle
Pagination61890-61904
Issue Number38
Volume Number7
dc.identifier.essn 1949-2553


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