Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for
cancer therapy. Here, we identify a subset of
non-small cell lung cancer (NSCLC) cell lines that survive in the absence of
glucose by internalizing and metabolizing extracellular
protein via macropinocytosis. Macropinocytosis is increased in these
glucose independent cells, and is regulated by
phosphoinositide 3-kinase (PI3K) activation of Rac-Pak signaling. Furthermore, inhibition of Rac-dependent macropinocytosis blocks
glucose-independent proliferation. We find that degradation of internalized
protein produces
amino acids, including
alanine, which generates TCA cycle and glycolytic intermediates in the absence of
glucose. In this process, the conversion of
alanine to
pyruvate by
alanine transaminase 2 (ALT2) is critical for survival during
glucose starvation. Collectively, Rac driven macropinocytosis of extracellular
protein is an adaptive metabolic pathway used by a subset of
lung cancers to survive states of
glucose deprivation, and may serve as a potential drug target for
cancer therapy.