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

By Cosimo Commisso, S. Davidson, Rengin G. Soydaner-Azeloglu, Seth J. Parker, Jurre J. Kamphorst, S. Hackett, Elda Grabocka, Michel Nofal, J. Drebin, Craig B. Thompson and 4 more. Nature, 2013

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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. 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.

Subfields: Cancer Research, Cell Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/c779d221ba8f6aa278c3a3c8376e4f9905059434

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Citations in the corpus

Autophagy, Metabolism, and Cancer (2015, positive): “Macropinocytosis and lysosomal degradation of albumin (and presumably other extracellular proteins) is an important survival mechanism for K-ras–driven pancreatic cancer (69, 70).”
Unraveling the mysteries of serum albumin—more than just a serum protein (2014, background): “The exact role of some incompletely characterized albumin-binding proteins (i.e., hnRNPs and calreticulin) in mediating albumin uptake remains to be determined.”
KRAS: feeding pancreatic cancer proliferation (2014, neutral): “A recent report demonstrated that PDAC cells expressing oncogenic KRAS utilized macropinocytosis to transport extracellular protein into the cell and that this endocytosed protein served as a source of glutamine [70].”
Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer (2016, methodology): “MIDs were corrected for natural isotope abundance as previously reported (Commisso et al., 2013).”
Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport (2014, background): “However, survival in the nutrient-limited conditions of actual tumors may require cells to engage alternative metabolic pathways, including degradation of proteins to supply carbon to the TCA cycle (Commisso et al., 2013).”
The biology, function, and biomedical applications of exosomes (2020, positive): “expression promote exosome uptake by macropinocytosis in human pancreatic cancer cells (27, 28).”
Organoid profiling identifies common responders to chemotherapy in pancreatic cancer (2018, background): “430 The poor response of PDAC patients to therapies has been attributed to neoplastic cell characteristics such 431 as cancer stem cells (17), redox metabolism (27) and intermediary metabolism (28, 29); and to non-cell 432 autonomous properties such as limited drug delivery (30-32), impaired intra-t”