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.
Highlights
Sustained rapid proliferation represents a major metabolic hurdle for cancer cells
We aim to summarize the mechanisms that govern macropinocytosis regulation in cancer cells, as well as to provide the latest findings supporting its important role as a nutrient supply pathway that enables tumor cell proliferation and survival
This study only addressed Na+/H+ exchangers (NHEs) inhibition of epidermal growth factor (EGF)-induced macropinocytosis in A431 cells, it is likely that similar mechanisms account for amiloride/ EIPA inhibition in the setting of other growth factors and in Ras-induced macropinocytosis, where H+ accumulation caused by increased metabolic activity and actin polymerization occurs, especially in cancer cells where the high metabolic rate is well known to promote acidification of the cell and the tumor microenvironment [45,46,47]
Summary
Sustained rapid proliferation represents a major metabolic hurdle for cancer cells. The challenge lies in balancing the towering energy and nutrient demands required for biomass production with the harsh nutrient-depleted conditions of the tumor microenvironment. It is not surprising that tumors have evolved the capacity to employ the same oncogenic signaling pathways [e.g., RAS, MYC, PI3-kinase (PI3K)] that trigger aberrant growth to control the metabolic rewiring that is necessary to adapt to a nutrient-deprived ecosystem [1]. A better understanding of the molecular mechanisms and metabolic adaptations that confer growth and survival advantages to cancer cells could lead to the discovery of novel therapeutic opportunities. One of the many adaptive strategies that cancer cells use to fulfill their metabolic demands is the ability to exploit alternative nutrient acquisition pathways [3]. The amoeboid organism Dictyostelium discoideum utilizes macropinocytic uptake to engulf fluid and nutrients during axenic growth [6].
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