Aldehyde dehydrogenase is used by cancer cells for energy metabolism

We found that non-small-cell lung cancer (NSCLC) cells express high levels of multiple aldehyde dehydrogenase (ALDH) isoforms via an informatics analysis of metabolic enzymes in NSCLC and immunohistochemical staining of NSCLC clinical tumor samples. Using a multiple reaction-monitoring mass spectrometry analysis, we found that multiple ALDH isozymes were generally abundant in NSCLC cells compared with their levels in normal IMR-90 human lung cells. As a result of the catalytic reaction mediated by ALDH, NADH is produced as a by-product from the conversion of aldehyde to carboxylic acid. We hypothesized that the NADH produced by ALDH may be a reliable energy source for ATP production in NSCLC. This study revealed that NADH production by ALDH contributes significantly to ATP production in NSCLC. Furthermore, gossypol, a pan-ALDH inhibitor, markedly reduced the level of ATP. Gossypol combined with phenformin synergistically reduced the ATP levels, which efficiently induced cell death following cell cycle arrest. The role of aldehyde dehydrogenase enzymes (ALDH) in the most common type of lung cancer cells offers new opportunities for treatment. ‘Non-small-cell lung cancer’ cells are found in around 80-90 per cent of lung cancers and are relatively insensitive to chemotherapy. The cancer cells are sustained by high levels of the energy-supplying molecule adenosine triphosphate (ATP). Researchers in South Korea led by Soo-Youl Kim at the National Cancer Center, Goyang, detected high levels of several forms of ALDH in the cancer cells. They uncovered a mechanism whereby the ALDH significantly contributed to the high ATP levels. A known inhibitor of ALDH enzymes called gossypol, combined with the drug phenformin, stopped cultured cancer cells from multiplying by ATP depletion and induced cell death through cell cycle arrest. The therapeutic potential of this new insight into the cancer cells' metabolism warrants further investigation.