Gautam Dhar, Suvajit Sen and Gautam Chaudhuri
Departments of Obstetrics and Gynecology and Molecular and Medical Pharmacology & Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California at Los Angeles, USA
Aggressive cancers exhibit high glucose to lactate conversion accompanied by acid secretion, a phenomenon popularly known as the Warburg effect. The acidic microenvironment and the alkaline cytosol create a proton-gradient (acid gradient) across the plasma membrane that represents proton-motive energy. There is strong in vivo physiological evidence which indicate that acid gradient can stimulate proliferation of tumors and is also supportive of their energy needs. However, direct biochemical evidence linking extracellular acid gradient to the generation of intracellular ATP have been lacking. We demonstrated that cancer cells can synthesize significant amounts of phosphate- bonds from phosphate in response to acid gradient across the plasma membrane. This phenomenon was observed even in the absence of glycolysis and mitochondrial ATP synthesis, and is unique to cancer. Assays with viable cancer cells and plasma membrane vesicles utilizing radioactive phosphate confirmed new phosphate-bond synthesis from phosphate (Pi), as well as localization of this activity to the plasma membrane. In addition to ATP, predominant formation of pyrophosphate (PPi) from Pi was observed when plasma membrane vesicles from cancer cells were subjected to transmembrane acid gradient. Cytosol from cancer cells were found capable of converting PPi to ATP, and also stimulating ATP synthesis from Pi from the vesicles. Acid gradient created through glucose metabolism by cancer cells, as observed in tumors, also proved critical for phosphate-bond synthesis. The findings suggest a role of acidic tumor milieu as a potential energy source. This pathway can be a prospective therapeutic target.