Selective regulation and cellular metabolism by the lactate transporter MCT4 in GBM

Hypoxia drives adaptive gene expression in glioblastoma (GBM), influencing tumor progression and metabolic reprogramming. This study investigated the hypoxic response of a patient-derived GBM cancer stem cell line, identifying key hypoxia-inducible genes such as SLC16A3, CA9, BNIP3, VEGFA, and NDRG1. SLC16A3 encodes the lactate transporter MCT4, whose expression has been implicated in biology of several cancers, including GBM. To evaluate role of MCT4, its expression was transiently reduced using siRNA resulting in an attenuated hypoxic induction of NDRG1 and SOX2, while sparing CA9 and BNIP3. Immunoblotting of GBM patient tissues revealed heterogeneous co-expression of MCT4 and NDRG1, highlighting a possible metabolic diversity within tumors. Moreover, metabolomic data of the cells showed dysregulated metabolites such as elevated stearic acid and decreased levels of D-( +)-2-phosphoglyceric acid, lactic acid, purine, pyridoxal, N,N,N-trimethyl lysine, and phosphatidylcholine (18:1/18:1) (del9-trans). Decreased intracellular lactate and increased acidity under hypoxic conditions, confirmed important role of MCT4 role in lactate transport and pH regulation. By establishing central role of MCT4 in hypoxia-driven processes, this study provides valuable insights into GBM metabolic plasticity and suggests that MCT4 might be potential therapeutic target.