Macropinocytosis: A Metabolic Adaptation to Nutrient Stress in Cancer

Abstract

Oncogenic mutations, such as Ras mutations, drive not only enhanced proliferation but also the metabolic adaptations that confer to cancer cells the ability to sustain cell growth in a harsh tumor microenvironment. These adaptations might represent metabolic vulnerabilities that can be exploited to develop novel and more efficient cancer therapies. Macropinocytosis is an evolutionarily conserved endocytic pathway that permits the internalization of extracellular fluid via large endocytic vesicles known as macropinosomes. Recently, macropinocytosis has been determined to function as a nutrient-scavenging pathway in Ras-driven cancer cells. Macropinocytic uptake of extracellular proteins, and their further degradation within endolysosomes, provides the much-needed amino acids that fuel cancer cell metabolism and tumor growth. Here, we review the molecular mechanisms that govern the process of macropinocytosis, as well as discuss recent work that provides evidence of the important role of macropinocytosis as a nutrient supply pathway in cancer cells.

Keywords: Ras; cancer metabolism; growth factors; macropinocytosis; nutrient uptake.

Figure 1

Schematic representation of extracellular protein uptake via macropinocytosis in cancer cells. Ras activation, either by growth factor stimulation or through oncogenic mutation, leads to increased membrane ruffling and macropinocytosis via activation of Rac1 and Cdc42, which in turn stimulate p21-activated kinase 1 (Pak1) to induce actin polymerization. Activation of Rac1 and Cdc42 is sensitive to changes in submembranous pH, and the activity of Na+/H+ exchangers (NHEs) and vacuolar H+-ATPase (V-ATPases) is crucial to maintaining pH homeostasis. Conversion of membrane phosphoinositides by PI3-kinase (PI3K) is also necessary for macropinocytosis. Macropinosomes containing extracellular proteins such as albumin and collagen are internalized and subsequently fuse with lysosomes. Lysosomal proteases (▲) allow the catabolism of extracellular proteins into free amino acids (a.a.) that can fuel the TCA cycle to promote cell growth and survival. mTORC1 finely regulates the utilization of extracellular protein-derived amino acids by inhibiting macropinocytosed protein catabolism when free a.a. are abundant. Yellow stars represent phosphorylation of growth factor receptors.