Metabolic alterations underlying Bevacizumab therapy in glioblastoma cells

// Vera Miranda-Gonçalves 1, 2, * , Diana Cardoso-Carneiro 1, 2, * , Inês Valbom 1, 2 , Fernanda Paula Cury 3 , Viviane Aline Silva 3 , Sara Granja 1, 2 , Rui M. Reis 1, 2, 3 , Fátima Baltazar 1, 2 and Olga Martinho 1, 2, 3 1 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal 2 ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal 3 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil * These authors have contributed equally to this work Correspondence to: Olga Martinho, email: olgamartinho@med.uminho.pt Keywords: anti-angiogenic therapy, Bevacizumab, glioblastoma, glycolytic metabolism Received: March 31, 2017     Accepted: September 21, 2017     Published: October 10, 2017 ABSTRACT Anti-VEGF therapy with Bevacizumab is approved for glioblastoma treatment, however, it is known that tumors acquired resistance and eventually became even more aggressive and infiltrative after treatment. In the present study we aimed to unravel the potential cellular mechanisms of resistance to Bevacizumab in glioblastoma in vitro models. Using a panel of glioblastoma cell lines we found that Bevacizumab is able to block the secreted VEGF by the tumor cells and be internalized to the cytoplasm, inducing cytotoxicity in vitro . We further found that Bevacizumab increases the expression of hypoxic (HIF-1α and CAIX) and glycolytic markers (GLUT1 and MCT1), leading to higher glucose uptake and lactate production. Furthermore, we showed that part of the consumed glucose by the tumor cells can be stored as glycogen, hampering cell dead following Bevacizumab treatment. Importantly, we found that this change on the glycolytic metabolism occurs independently of hypoxia and before mitochondrial impairment or autophagy induction. Finally, the combination of Bevacizumab with glucose uptake inhibitors decreased in vivo tumor growth and angiogenesis and shift the expression of glycolytic proteins. In conclusion, we reported that Bevacizumab is able to increase the glucose metabolism on cancer cells by abrogating autocrine VEGF in vitro . Define the effects of anti-angiogenic drugs at the cellular level can allow us to discover ways to revert acquired resistance to this therapeutic approaches in the future.