Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells

Abstract

Oncogenic Ras has previously been shown to promote macropinocytosis; here it is demonstrated that this process allows tumour cells to use extracellular proteins to generate amino acids necessary to support tumour growth. This paper describes a previously unrecognized pathway of nutrient supply to cancer cells. Oncogenic Ras proteins are known to promote macropinocytosis, an endocytic process by which extracellular fluid and its contents are internalized into cells through vesicles known as macropinosomes. Dafna Bar-Sagi and colleagues now demonstrate that Ras-transformed cells can use this process to 'feed' on extracellular protein. The macropinocytosed protein undergoes degradation, giving rise to free amino acids necessary to support tumour growth. This finding suggests that inhibition of macropinocytosis may be effective against a subset of cancers. Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown1,2,3. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.