Proton export upregulates aerobic glycolysis.

Area of Science:

• Cancer Biology
• Cell Metabolism
• Oncology

Background:

• Aggressive cancers exhibit high rates of aerobic glycolysis (Warburg Effect), fermenting glucose to lactate even with oxygen.
• This is often attributed to increased glycolytic enzyme expression, but cytoplasmic alkalization may also play a role.

Purpose of the Study:

• To investigate if proton export alone can drive aerobic glycolysis and enhance cancer aggressiveness.
• To test the hypothesis that H+ expulsion can increase intracellular pH and promote glucose metabolism.

Main Methods:

• Stable transfection of cancer cells (MCF-7, U2-OS, HEK293) with proton exporters (PMA1, CA-IX).
• Measurement of glucose consumption, lactate production, and extracellular acidification rate.
• In vitro migration/invasion assays and in vivo tumor formation/metastasis studies.
• Administration of oral buffers to neutralize tumor acidity.

Main Results:

• Expression of proton exporters enhanced aerobic glycolysis and increased intracellular pH.
• Increased glycolytic flux was observed upstream of pyruvate kinase.
• Engineered cells showed increased in vitro migration/invasion and in vivo tumor aggressiveness with higher metastasis rates.
• Tumor acidity neutralization reduced metastatic burden.

Conclusions:

• Increased export of H+ equivalents can drive aerobic glycolysis and the Warburg phenotype, even without oncogenic mutations.
• Proton exporter activity is sufficient to alter cancer metabolism and confer a survival advantage.
• Targeting tumor acidity presents a potential therapeutic strategy to reduce cancer progression and metastasis.