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 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.

The soft underbelly of tumor cells

“…For certain type of tumors, such as tumors expressing oncogenic Ras, macropinocytosis represents an important route of nutrient uptake. Pharmacological inhibition of macropinocytosis compromises the growth of Ras-transformed tumor xenografts [6]. The present work provides support for the authors' hypothesis that gain-and loss-of-function mutants in glioma could lead to unique cellular properties of GCs that are weak or absent in other cell types.…”

Involvement of a Rac1-Dependent Macropinocytosis Pathway in Plasmid DNA Delivery by Electrotransfection

“…Vesicles associated with macropinocytosis are called macropinosomes, which are large (0.2-5 mm in diameter) uncoated vesicles that allow cells to internalize a significant amount of extracellular solutes, especially macromolecules. 51,52 Macropinocytosis is involved in many important cellular events, including amino acid uptake, 53 entry of viral particles, 54 and antigen responses of immune cells. 49 The present study was designed to determine the role played by macropinocytosis in electrotransfection and how the small GTPase Rac1 regulates the endocytic process.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…In vitro, it is rather dif fi cult to ap pre ci ate this com plex ity, be cause of the lack of het ero gene ity, both meta bolic [5] and cel lu lar [251], but also be cause of the lack of en vi ron men tal clues [8], as well as cel lu lar po lar iza tion [255]. The re quire ment of grow ing cells in vitro with con cen tra tion of glu cose far ex ceed ing the phys i o log i cal lev els also leads to spe cific meta bolic adap ta tions [256][257][258]. While the cur rent cell cul ture con di tions are mostly aimed at al low ing cel lu lar pro lif er a tion at a dou bling rate gen er ally higher than 24 h, it is now nec es sary to de velop more ac cu rate cell cul ture con di tions to mimic nu tri ent con di tions re ca pit u lat ing the tu mor mi lieu [256].…”