Abstract
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.
Highlights
It has been well established that tumor cells have altered metabolism compared to non-proliferating cells
To identify how lung cancer cells adapt their metabolism to overcome glucose starvation, we cultured a panel of non-small cell lung cancer (NSCLC) cells lines in glucose-free medium containing dialyzed fetal bovine serum, and measured cell viability following 48 h of glucose deprivation
The addition of albumin did not increase the viability of the cell lines that are addicted to glucose (Figure 1D), suggesting that only glucose independent cells can utilize extracellular protein as a fuel source
Summary
It has been well established that tumor cells have altered metabolism compared to non-proliferating cells. Recent reports have demonstrated that glucose levels vary in solid tumors, and glucose concentrations are often decreased in tumors compared to the surrounding normal tissue [4,5,6,7]. This deficiency of glucose in the tumor microenvironment makes it necessary for cancer cells to adopt alternative metabolic pathways to support tumor growth. In the absence of glucose, tumors rely on alternate fuel sources to support cell growth in nutrient-poor environments [8,9]. Some cancer cells are dependent on glutaminolysis to generate glutamate and α-ketoglutarate which can drive the tricarboxylic acid (TCA) cycle and ATP production
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