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Published on: August 19, 2021
Non-apoptotic cell death associated with perturbations of macropinocytosis
William A Maltese1, Jean H Overmeyer1
1Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences Toledo, OH, USA.
Abstract:
Although macropinocytosis is widely recognized as a distinct form of fluid-phase endocytosis in antigen-presenting dendritic cells, it also occurs constitutively in many other normal and transformed cell types. Recent studies have established that various genetic or pharmacological manipulations can hyperstimulate macropinocytosis or disrupt normal macropinosome trafficking pathways, leading to accumulation of greatly enlarged cytoplasmic vacuoles. In some cases, this extreme vacuolization is associated with a unique form of non-apoptotic cell death termed "methuosis," from the Greek methuo (to drink to intoxication). It remains unclear whether cell death related to dysfunctional macropinocytosis occurs in normal physiological contexts. However, the finding that some types of cancer cells are particularly vulnerable to this unusual form of cell death has raised the possibility that small molecules capable of altering macropinosome trafficking or function might be useful as therapeutic agents against cancers that are resistant to drugs that work by inducing apoptosis. Herein we review examples of cell death associated with dysfunctional macropinocytosis and summarize what is known about the underlying mechanisms.
Insights
Macropinocytosis, a cellular process, can lead to cell death called methuosis when disrupted. This discovery offers potential new cancer therapies targeting drug-resistant cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Macropinocytosis is a form of endocytosis observed in dendritic cells and other cell types.
- Dysfunctional macropinocytosis can cause excessive vacuole formation within cells.
- This vacuolization is linked to a non-apoptotic cell death pathway known as methuosis.
Purpose of the Study:
- To review cell death mechanisms associated with disrupted macropinocytosis.
- To explore the potential of targeting macropinocytosis for cancer therapy.
Main Methods:
- Literature review of studies on macropinocytosis and cell death.
- Analysis of genetic and pharmacological manipulations affecting macropinosome trafficking.
- Examination of cell death pathways, including methuosis.
Main Results:
- Constitutive macropinocytosis occurs in various cell types beyond dendritic cells.
- Hyperstimulation or disruption of macropinocytosis leads to enlarged cytoplasmic vacuoles.
- Methuosis is a distinct form of non-apoptotic cell death associated with extreme vacuolization.
- Some cancer cells exhibit particular susceptibility to methuosis.
Conclusions:
- Dysfunctional macropinocytosis can induce cell death (methuosis).
- Targeting macropinocytosis pathways presents a potential therapeutic strategy for apoptosis-resistant cancers.
- Further research is needed to understand the physiological roles and therapeutic applications of modulating macropinocytosis.
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