ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)
MCT1 as a novel target for the treatment of osteolytic bone metastases
Sofia Avnet 1 , Silvia Lemma 1, , Gemma Di Pompo 1, , Martina Sboarina 3 , Paolo Porporato 3 , Jhudit Perez-Escuredo 3 , Pierre Sonveaux 3 & Nicola Baldini 1,
1Istituto Ortopedico Rizzoli, Bologna, Italy; 2University of Bologna, Bologna, Italy; 3University of Louvain (UCL), Brussels, Belgium.
Bone metastasis (BM) is a dismal complication of cancer, occurring frequently in patients with advanced breast carcinoma. During metastatic progression, carcinoma cells harness osteoclast (OC) activity, promoting osteolysis. To adapt to hypoxia and/or to support proliferation, carcinoma cells adopt primarily glycolysis for energy production, therefore releasing lactic acid in the microenvironment through monocarboxylate transporter 4 (MCT4). Stressed by tumor cells, osteoblasts (OB) can also switch to a more glycolytic metabolism, further promoting lactate release. Here, we hypothesized that extracellular lactate is uptaken by OC through MCT1 to fuel oxydative phosphorylation (OXPHOS), thereby promoting the osteolytic process. We used human primary cultures of OC and OB, wt breast carcinoma MDA-MB-231 (wtMDA-BM-231) cells and MDA-MB-231 clone prone to form bone metastasis (bmMDA-MB-231). OC differentiation and activity were analyzed by TRAP/nuclei staining, and osteolyse assay. MCTs expression was evaluated by RT-qPCR and western Blot. Metabolic analyses were performed by Seahorse XF96 and CMA600 analyzers, JC-1 staining and ATP assay. We found an increased expression of MCT1 in OC during the differentiation process, a dose-dependent uptake of 14C-lactate by OC and that OC rely on OXPHOS as the main source for energy production, whereas monocytic precursors have a higher glycolytic rate. Finally, exposure of OC to sodium lactate promoted OXPHOS. As a confirmation of our hypothesis, OB, wtMDA-MB-231 and bmMDA-MB-231 express high levels of MCT4 and do not express MCT1. Our data demonstrate that lactate released by tumor cells and OB into the BM microenvironment can be uptaken by OC through MCT1 to promote the BM osteolytic process. MCT1 is therefore a promising target for the treatment of BM.
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Bone Abstracts
ISSN 2052-1219 (online)
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