Abstract
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells via 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 unknown1-3. Here we show that Ras-transformed cells utilize 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 tumor nutrient uptake, its pharmacological inhibition compromised the growth of Ras-transformed pancreatic tumor 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 anti-cancer therapies.
Highlights
The macropinocytic internalization and subsequent degradation of albumin could in principle lead to the generation of amino acids that sustain tumor cell bioenergetics and macromolecular synthesis[15]
DQ-BSA fluorescence was detected within macropinosomes after a 1 hour chase in MIA PaCa-2 and T24 cells, indicating that these trafficking events were occurring in cancer cells harboring endogenous oncogenic Ras mutations (Supplementary Fig. 5)
The degradation of macropinocytosed albumin was dependent on lysosomal hydrolases because treatment of MIA PaCa-2 and NIH 3T3 [KRasV12] cells with bafilomycin A1 prevented the degradation of DQ-BSA (Supplementary Fig. 6)
Summary
The macropinocytic internalization and subsequent degradation of albumin could in principle lead to the generation of amino acids that sustain tumor cell bioenergetics and macromolecular synthesis[15]. Pancreatic adenocarcinoma-derived human MIA PaCa-2 cells, which are homozygous for the K-RasG12C allele[4], displayed appreciably higher levels of TMR-dextran uptake compared to BxPC-3 cells, which express wild-type K-Ras (Fig. 1a, b)[5].
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