Abstract
Internalization and degradation of extracellular protein supplies cancer cells with amino acids.
Major finding: Internalization and degradation of extracellular protein supplies cancer cells with amino acids.
Concept: Macropinocytosed proteins serve as a source of glutamine for RAS-mutant cancer cells.
Impact: A subset of cancers may be sensitive to inhibition of macropinocytosis.
Overexpression of some oncogenes has been observed to induce macropinocytosis, a type of endocytosis in which extracellular fluid and its contents are internalized by large vesicles, but the physiologic relevance of macropinocytosis and its role in cancer are unclear. Commisso and colleagues show that increased macropinocytosis is a hallmark of cancer cells endogenously expressing mutant RAS proteins both in vitro and in vivo and that high levels of macropinocytosis are dependent on oncogenic RAS signaling. Given that proteins account for the majority of soluble compounds in extracellular fluid, it is possible that internalization and subsequent degradation of extracellular proteins might serve as a source of amino acids in RAS-transformed cells. Indeed, serum albumin, the most abundant extracellular protein, was internalized and intracellularly degraded, which led to an increase in intracellular levels of glutamate and α-ketoglutarate, metabolites of the amino acid glutamine. Carbon tracing experiments indicated that extracellular protein–derived amino acids entered multiple metabolic pathways, suggesting that internalization and degradation of extracellular protein is necessary to meet the metabolic demands of RAS-mutant cells, particularly their increased dependence on glutamine. Consistent with this possibility, albumin supplementation rescued the inhibitory effects of glutamine deprivation on RAS-mutant cell growth, which could be reversed by pharmacologic inhibition of macropino-cytosis with 5-(N-ethyl-N-isopropyl)amiloride (EIPA). Importantly, administration of EIPA slowed the growth of RAS-mutant xenografts in vivo, in some cases even inducing regression, providing further evidence that macropinocytic nutrient uptake is essential for the survival of RAS-driven tumors. Of note, an oncogenic SRC mutant was also found to induce macropinocytosis of albumin to augment intracellular glutamine levels, suggesting that this phenomenon is not only a consequence of mutant RAS activity. Induction of macropinocytosis by oncogenic signaling pathways may therefore create a potential therapeutic target in a subset of human cancers.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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