pH sensing and regulation in cancer

Area of Science:

• Cellular Biology
• Oncology
• Biochemistry

Background:

• Cells tightly regulate intracellular pH (pHi) via proton pumps and transporters, influenced by intracellular pH sensors.
• Extracellular acidification, a consequence of pHi regulation, impacts cellular functions through acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs).

Purpose of the Study:

• To review major proton-sensing molecules at the plasma membrane.
• To discuss their downstream effects on cancer cell migration and metastasis.
• To explore the complex mechanisms of pH signal transduction in cancer.

Main Methods:

• Review of existing literature on proton sensing mechanisms.
• Analysis of the role of specific proton-sensing GPCRs (GPR4, TDAG8, OGR1) in tumorigenesis and invasion.
• Examination of cellular pH homeostasis mechanisms (monocarboxylate, bicarbonate, proton transporters).

Main Results:

• Proton-sensing GPCRs regulate cancer cell invasion, actin dynamics (cofilin, talin), migration, and metastasis.
• A mechanistic disconnect exists between intracellular pH homeostasis transporters and extracellular proton sensors.
• Tumor acidosis is a common physical hallmark with potential therapeutic implications.

Conclusions:

• Understanding extracellular pH sensing is crucial for cancer progression.
• Targeting tumor acidosis presents a potential therapeutic strategy.
• Further research is needed to elucidate the complex pH signaling pathways in cancer cells.