Journal
NATURE
Volume 497, Issue 7451, Pages 633-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12138
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Funding
- National Institutes of Health (NIH) [R01CA055360, 5 P30CA016087-32]
- Canadian Institutes of Health Research
- AACR provided by the Pancreatic Cancer Action Network
- Burroughs Wellcome Fund
- Damon Runyon Cancer Research Foundation
- Smith Family
- Stern family
- Broad Institute
- National Cancer Institute [P01-CA117969, P30-CA14051-39]
- Hope Funds for Cancer Research Fellowship [HFCR-11-03-01]
- Stand Up To Cancer (SU2C) Pancreatic Cancer Dream Team Award
- NICHD
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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 unknown(1-3). 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.
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