title: Acid gradient across plasma membrane can drive phosphate bond synthesis in cancer cells: acidic tumor milieu as a potential energy source.
abstract: Aggressive cancers exhibit an efficient conversion of high amounts of glucose to lactate 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. Increasing experimental data from physiological relevant models suggest that acid gradient stimulates tumor proliferation, and can also support its energy needs. However, direct biochemical evidence linking extracellular acid gradient to generation of intracellular ATP are missing. In this work, we demonstrate that cancer cells can synthesize significant amounts of phosphate-bonds from phosphate in response to acid gradient across plasma membrane. The noted phenomenon exists in absence of glycolysis and mitochondrial ATP synthesis, and is unique to cancer. Biochemical assays using viable cancer cells, and purified plasma membrane vesicles utilizing radioactive phosphate, confirmed phosphate-bond synthesis from free phosphate (Pi), and also localization of this activity to the plasma membrane. In addition to ATP, predominant formation of pyrophosphate (PPi) from Pi was also observed when plasma membrane vesicles from cancer cells were subjected to trans-membrane acid gradient. Cancer cytosols were found capable of converting PPi to ATP, and also stimulate 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. In brief, these observations reveal a role of acidic tumor milieu as a potential energy source and may offer a novel therapeutic target.
authors: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1740, United States of America.
authors: Gautam
authors: G
authors: Dhar
authors: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1740, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, CA, United States of America.
authors: Suvajit
authors: S
authors: Sen
authors: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1740, United States of America; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1740, United States of America; Jonsson Comprehensive Cancer Center, Los Angeles, CA, United States of America.
authors: Gautam
authors: G
authors: Chaudhuri
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism*; D011756:Diphosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport; D007700:Kinetics; D019344:Lactic Acid / Q000096:biosynthesis; D010710:Phosphates / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D011522:Protons
chemical_list: D011756:Diphosphates; D010710:Phosphates; D010761:Phosphorus Radioisotopes; D011522:Protons; D019344:Lactic Acid; C107241:diphosphoric acid; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005947:Glucose