Follow the ATP: Tumor Energy Production: A Perspective

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.

Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells

“…There are four major ATP supply methods – oxidative phosphorylation, glutaminolysis, autophagy, and glycolysis. 25, 53 Combining our results shown in Figure 2c and the essential characteristics of cancer cells, we concluded that because cancer cells only maintain low levels of oxidative phosphorylation, glycolysis was blocked by the decrease in glucose, and glutaminolysis can only produce low levels of ATP, and autophagy was the likely mechanism of ATP upregulation caused by oridonin treatment. The results of autophagy-related biomarker analysis and transmission electron microscopy analysis confirmed the hypothesis (Figure 4; Supplementary Figure 3) that autophagy is induced by oridonin in p53-mutated CRC cells.…”

“…There are four ATP sources in normal cells, including oxidative phosphorylation, glycolysis, glutaminolysis, and autophagy. 25 The phenotype of the cancer cells indicated that oxidative phosphorylation and glutaminolysis cannot be the sources of the high intracellular ATP levels. Our finding of glucose uptake inhibition also suggested that glycolysis was not responsible for the ATP upregulation.…”

Induction of apoptosis by ethanol extract of <i>Evodia rutaecarpa</i> in HeLa human cervical cancer cells <i>via</i> activation of AMP-activated protein kinase

“…When the cancer cells are in a glucose-depleted condition, they maintain ATP synthesis through OXPHOS and activate the catabolic pathways, including the oxidation of fatty acids and amino acids (6,33). In addition, cancer cells are more vulnerable to ROS generally generated from mitochondria compared to normal cells (5,34).…”

Glutamine and glutaminolysis are required for efficient replication of infectious spleen and kidney necrosis virus in Chinese perch brain cells

“…Glutamine can be metabolized to α-KG to provide ATP through glutaminolysis [28]. Indeed, Chambers et al .…”