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The V-ATPases in cancer and cell death
Fangquan Chen1, Rui Kang2, Jiao Liu3
1DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
Abstract:
Transmembrane ATPases are membrane-bound enzyme complexes and ion transporters that can be divided into F-, V-, and A-ATPases according to their structure. The V-ATPases, also known as H+-ATPases, are large multi-subunit protein complexes composed of a peripheral domain (V1) responsible for the hydrolysis of ATP and a membrane-integrated domain (V0) that transports protons across plasma membrane or organelle membrane. V-ATPases play a fundamental role in maintaining pH homeostasis through lysosomal acidification and are involved in modulating various physiological and pathological processes, such as macropinocytosis, autophagy, cell invasion, and cell death (e.g., apoptosis, anoikis, alkaliptosis, ferroptosis, and lysosome-dependent cell death). In addition to participating in embryonic development, V-ATPase pathways, when dysfunctional, are implicated in human diseases, such as neurodegenerative diseases, osteopetrosis, distal renal tubular acidosis, and cancer. In this review, we summarize the structure and regulation of isoforms of V-ATPase subunits and discuss their context-dependent roles in cancer biology and cell death. Updated knowledge about V-ATPases may enable us to design new anticancer drugs or strategies.
Insights
Vacuolar ATPases (V-ATPases) are crucial for cellular pH balance and various cell processes. Dysfunctional V-ATPases are linked to diseases like cancer, offering potential therapeutic targets.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- V-ATPases are essential transmembrane enzyme complexes and ion transporters.
- They are categorized into F-, V-, and A-ATPases based on structure.
- V-ATPases, or H+-ATPases, comprise peripheral (V1) and membrane-integrated (V0) domains.
Purpose of the Study:
- To review the structure and regulation of V-ATPase subunit isoforms.
- To discuss the context-dependent roles of V-ATPases in cancer biology and cell death.
- To highlight the potential of V-ATPases as therapeutic targets.
Main Methods:
- Literature review of V-ATPase structure, regulation, and function.
- Analysis of V-ATPase involvement in physiological and pathological processes.
- Synthesis of current knowledge on V-ATPase isoforms in cancer and cell death.
Main Results:
- V-ATPases are critical for lysosomal acidification and pH homeostasis.
- They modulate key cellular processes including macropinocytosis, autophagy, and various forms of cell death.
- Dysfunctional V-ATPases are implicated in neurodegenerative diseases, osteopetrosis, renal tubular acidosis, and cancer.
Conclusions:
- Understanding V-ATPase structure and regulation is vital.
- V-ATPases play multifaceted roles in cancer development and cell death.
- Targeting V-ATPases may lead to novel anticancer drug development and therapeutic strategies.
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