Gastric cancer depends on aldehyde dehydrogenase 3A1 for fatty acid oxidation

The major source of ATP in cancer cells remains unclear. Here, we examined energy metabolism in gastric cancer cells and found increased fatty acid oxidation and increased expression of ALDH3A1. Metabolic analysis showed that lipid peroxidation by reactive oxygen species led to spontaneous productio...

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Bibliographic Details
Published inScientific reports Vol. 9; no. 1; pp. 16313 - 12
Main Authors Lee, Jae-Seon, Kim, Seung Hwa, Lee, Soohyun, Kang, Joon Hee, Lee, Seon-Hyeong, Cheong, Jae-Ho, Kim, Soo-Youl
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 08.11.2019
Nature Publishing Group UK
Subjects
4-Hydroxynonenal
Adenosine Triphosphate - biosynthesis
Aldehyde dehydrogenase
Aldehyde Dehydrogenase - deficiency
Aldehyde Dehydrogenase - genetics
Aldehyde Dehydrogenase - metabolism
Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation - drug effects
Electron transport chain
Energy metabolism
Fatty acids
Fatty Acids - metabolism
Female
Gastric cancer
Gene Knockdown Techniques
Gossypol
Gossypol - pharmacology
Humans
Lipid peroxidation
Male
Mice
Mitochondria
NADH
NADH-ubiquinone oxidoreductase
Oxidation
Oxidation-Reduction
Oxidative phosphorylation
Phenformin - pharmacology
Phosphorylation
Reactive oxygen species
siRNA
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
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Summary:The major source of ATP in cancer cells remains unclear. Here, we examined energy metabolism in gastric cancer cells and found increased fatty acid oxidation and increased expression of ALDH3A1. Metabolic analysis showed that lipid peroxidation by reactive oxygen species led to spontaneous production of 4-hydroxynonenal, which was converted to fatty acids with NADH production by ALDH3A1, resulting in further fatty acid oxidation. Inhibition of ALDH3A1 by knock down using siRNA of ALDH3A1 resulted in significantly reduced ATP production by cancer cells, leading to apoptosis. Oxidative phosphorylation by mitochondria in gastric cancer cells was driven by NADH supplied via fatty acid oxidation. Therefore, blockade of ALDH3A1 together with mitochondrial complex I using gossypol and phenformin led to significant therapeutic effects in a preclinical gastric cancer model.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-52814-1