Title:Follow the ATP: Tumor Energy Production: A Perspective
Volume: 14
Issue: 9
Author(s): Bryan T. Oronsky, Neil Oronsky, Gary R. Fanger, Christopher W. Parker, Scott Z. Caroen, Michelle Lybeck and Jan J. Scicinski
Affiliation:
Keywords:
ATP, energy restriction, glycolysis, reactive oxygen species, warburg effect.
Abstract: As early as the 1920s, the eminent physician and chemist, Otto Warburg, nominated for a second Nobel Prize for his work on
fermentation, observed that the core metabolic signature of cancer cells is a high glycolytic flux. Warburg averred that the prime mover
of cancer is defective mitochondrial respiration, which drives a switch to an alternative energy source, aerobic glycolysis in lieu of
Oxidative Phosphorylation (OXPHOS), in an attempt to maintain cellular viability and support critical macromolecular needs. The cell,
deprived of mitochondrial ATP production, must reprogram its metabolism as a secondary survival mechanism to maintain sufficient
ATP and NADH levels for macromolecule production, membrane integrity and DNA synthesis as well as maintenance of membrane
ionic gradients.
A time-tested method to identify and disrupt criminal activity is to “follow the money” since the illicit proceeds from crime are required
to underwrite it. By analogy, strategies to target cancer involve following and disrupting the flow of ATP and NADH, the energetic and
redox “currencies” of the cell, respectively, since the tumor requires high levels of ATP and NADH, not only for metastasis and
proliferation, but also, on a more basic level, for survival. Accordingly, four broad ATP reduction strategies to impact and potentially
derail cancer energy production are highlighted herein: 1) small molecule energy-restriction mimetic agents (ERMAs) that target various
aspects of energy metabolism, 2) reduction of energy ‘subsidization’ with autophagy inhibitors, 3) acceleration of ATP turnover to
increase energy inefficiency, and 4) dietary energy restriction to limit the energy supply.
