title: Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Commisso
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Rengin G
authors.initials: RG
authors.lastname: Soydaner-Azeloglu
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Parker
authors.forename: Jurre J
authors.initials: JJ
authors.lastname: Kamphorst
authors.forename: Sean
authors.initials: S
authors.lastname: Hackett
authors.forename: Elda
authors.initials: E
authors.lastname: Grabocka
authors.forename: Michel
authors.initials: M
authors.lastname: Nofal
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Drebin
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002244:Carbon / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005973:Glutamine / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010873:Pinocytosis; D059748:Proteolysis
chemical_list: D000596:Amino Acids; D005973:Glutamine; D002244:Carbon; D015689:Oncogene Protein p21(ras)