Journal
ONCOTARGET
Volume 7, Issue 31, Pages 49397-49410Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10354
Keywords
aldehyde dehydrogenase; NSCLC; gossypol; phenformin; cancer metabolism
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Funding
- National Cancer Center of Korea [NCC1410670]
- NRF Multi-Omics Program [2012M3A9B9036679]
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Among ALDH isoforms, ALDH1L1 in the folate pathway showed highly increased expression in non-small-cell lung cancer cells (NSCLC). Based on the basic mechanism of ALDH converting aldehyde to carboxylic acid with by-product NADH, we suggested that ALDH1L1 may contribute to ATP production using NADH through oxidative phosphorylation. ALDH1L1 knockdown reduced ATP production by up to 60% concomitantly with decrease of NADH in NSCLC. ALDH inhibitor, gossypol, also reduced ATP production in a dose dependent manner together with decrease of NADH level in NSCLC. A combination treatment of gossypol with phenformin, mitochondrial complex I inhibitor, synergized ATP depletion, which efficiently induced cell death. Pre-clinical xenograft model using human NSCLC demonstrated a remarkable therapeutic response to the combined treatment of gossypol and phenformin.
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