Targeting pH regulating proteins for cancer therapy-Progress and limitations.

Area of Science:

• Oncology
• Cell Physiology
• Biochemistry

Background:

• Tumour acidity, caused by metabolic changes and poor vascularization, distinguishes cancer cells.
• Altered intracellular pH (pH_i) disrupts protein function and cellular processes.
• Cancer cells maintain alkaline pH_i despite external acidification through enhanced pH regulatory machinery.

Purpose of the Study:

• To synthesize recent advances in understanding tumour pH regulation under normoxic and hypoxic conditions.
• To focus on disrupting tumour growth, survival, and metastasis by targeting pH regulatory mechanisms.
• To explore interactions between tumour acidity and other cell types for therapeutic applications like immunotherapy.

Main Methods:

• Review and synthesis of recent research on tumour pH regulation.
• Analysis of pH-regulating proteins including Na⁺/H⁺ exchangers (NHEs), carbonic anhydrases (CAs), Na⁺/HCO₃^- co-transporters (NBCs), and monocarboxylate transporters (MCTs).
• Examination of normoxic and hypoxic pH regulatory mechanisms in cancer cells.

Main Results:

• Redundancy among pH-regulating proteins (NHEs, CAs, NBCs, MCTs) prevents effective tumour pH_i disruption via single-target inhibition.
• Tumour cells enhance their pH regulatory capacity through oncogenic or hypoxia-induced modifications.
• Interactions between tumour acidity and other cells, such as immune cells, are crucial for therapeutic strategies.

Conclusions:

• Targeting tumour acidity offers a promising therapeutic avenue for cancer treatment.
• Overcoming protein redundancy in pH regulation is essential for developing effective therapies.
• Further research into pH manipulation and its interaction with the tumour microenvironment is needed to advance cancer treatment.