BACKGROUND.- Cancer cells from solid tumors become metabolically stressed, when nutrients are insufficient within poorly vascularized regions. Metabolic stress results from severe deprivation of oxygen, glutamine and glucose, partly through excessive reactive oxygen species (ROS) production. Mutant BRAF can stimulate the accumulation of hypoxia-inducible factor-1alpha (HIF-1α) in physiological glucose and supplementation with supra-physiological glutamine in melanoma cells (Kumar SM et al, Cancer Res. 2007;67:3177-84).Although HIF1α reprograms melanomas to become highly glycolytic, this can be impaired in a microenvironment with sub-physiological levels of glutamine and glucose (Kwon SJ, Lee YJ.Clin Cancer Res. 2005;11:4694-700).,because melanomas require glycolysis and mitochondrial glutamine utilization. PURPOSE.- To compare proliferation and survival in response to glutamine and glucose restriction in wt-BRAF or mutant BRAF melanoma. EXPERIMENTAL. Determination of metabolic activity/proliferation and cell survival by fluorometric assays and crystal violet staining. RESULTS.- Glutamine depletion diminished survival even in physiological 5 mM glucose, particularly during hypoxia. However, 2.5 mM glucose or exogenous pyruvate when added together with another anti-oxidant N-acetylcysteine (NAC) partly substituted for glutamine in normoxic wt-BRAF cells. A much lower attenuation was seen in glutamine-depleted mutant BRAF cells when supplemented with NAC and pyruvate, particularly, under hypoxia. CONCLUSIONS.-1) glutamine restriction decreases metabolic activity and tumor cell survival, irrespective of BRAF status, being more toxic to mut-BRAF cells, either under hypoxia or in physiological glucose and normoxia,. 2) Antagonizing glutamine addiction may decrease tumor recurrence if combined with anti-BRAF targeted therapy.

Citation Format: Manuel Rieber, Valery Chavez-Perez, Mary Strasberg-Rieber. BRAF status and low glutamine/glucose influence glutamine addiction modulated by oxidative stress in human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3049. doi:10.1158/1538-7445.AM2015-3049

©2015 American Association for Cancer Research.
2015