title: Effects of sorafenib on energy metabolism in breast cancer cells: role of AMPK-mTORC1 signaling.
abstract: In this study, we investigated the effects and the underlying molecular mechanisms of the multi-kinase inhibitor sorafenib in a panel of breast cancer cell lines. Sorafenib inhibited cell proliferation and induced apoptosis through the mitochondrial pathway. These effects were neither correlated with modulation of MAPK and AKT pathways nor dependent on the ERα status. Sorafenib promoted an early perturbation of mitochondrial function, inducing a deep depolarization of mitochondrial membrane, associated with drop of intracellular ATP levels and increase of ROS generation. As a response to this stress condition, the energy sensor AMPK was rapidly activated in all the cell lines analyzed. In MCF-7 and SKBR3 cells, AMPK enhanced glucose uptake by up-regulating the expression of GLUT-1 glucose transporter, as also demonstrated by AMPKα1 RNA interference, and stimulated aerobic glycolysis thus increasing lactate production. Moreover, the GLUT-1 inhibitor fasentin blocked sorafenib-induced glucose uptake and potentiated its cytotoxic activity in SKBR3 cells. Persistent activation of AMPK by sorafenib finally led to the impairment of glucose metabolism both in MCF-7 and SKBR3 cells as well as in the highly glycolytic MDA-MB-231 cells, resulting in cell death. This previously unrecognized long-term effect of sorafenib was mediated by AMPK-dependent inhibition of the mTORC1 pathway. Suppression of mTORC1 activity was sufficient for sorafenib to hinder glucose utilization in breast cancer cells, as demonstrated by the observation that the mTORC1 inhibitor rapamycin induced a comparable down-regulation of GLUT-1 expression and glucose uptake. The key role of AMPK-dependent inhibition of mTORC1 in sorafenib mechanisms of action was confirmed by AMPKα1 silencing, which restored mTORC1 activity conferring a significant protection from cell death. This study provides insights into the molecular mechanisms driving sorafenib anti-tumoral activity in breast cancer, and supports the need for going on with clinical trials aimed at proving the efficacy of sorafenib for breast cancer treatment.
authors: Department of Clinical and Experimental Medicine, University of Parma, Via Volturno, 39, Parma 43125, Italy. claudia.fumarola@unipr.it
authors: Claudia
authors: C
authors: Fumarola
authors: Cristina
authors: C
authors: Caffarra
authors: Silvia
authors: S
authors: La Monica
authors: Maricla
authors: M
authors: Galetti
authors: Roberta R
authors: RR
authors: Alfieri
authors: Andrea
authors: A
authors: Cavazzoni
authors: Elena
authors: E
authors: Galvani
authors: Daniele
authors: D
authors: Generali
authors: Pier Giorgio
authors: PG
authors: Petronini
authors: Mara A
authors: MA
authors: Bonelli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D015536:Down-Regulation; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D000076222:Mechanistic Target of Rapamycin Complex 1; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C533793:fasentin; D009536:Niacinamide; D000255:Adenosine Triphosphate; D000077157:Sorafenib; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D005947:Glucose