Rationale: The activity of aldehyde dehydrogenase 7A1 (ALDH7A1), an enzyme that catalyzes the lipid peroxidation of fatty aldehydes was found to be upregulated in pancreatic ductal adenocarcinoma (PDAC). ALDH7A1 knockdown significantly reduced tumor formation in PDAC. We raised a question how ALDH7A1 contributes to cancer progression. Methods: To answer the question, the role of ALDH7A1 in energy metabolism was investigated by knocking down and knockdown gene in mouse model, because the role of ALDH7A1 has been reported as a catabolic enzyme catalyzing fatty aldehyde from lipid peroxidation to fatty acid. Oxygen consumption rate (OCR), ATP production, mitochondrial membrane potential, proliferation assay and immunoblotting were performed. In in vivo study, two human PDAC cell lines were used for pre-clinical xenograft model as well as spontaneous PDAC model of KPC mice was also employed for anti-cancer therapeutic effect. Results: ALDH7A1 knockdown significantly reduced tumor formation with reduction of OCR and ATP production, which was inversely correlated with increase of 4-hydroxynonenal. This implies that ALDH7A1 is critical to process fatty aldehydes from lipid peroxidation. Overall survival of PDAC is doubled by cross breeding of KPC (KrasG12D; Trp53R172H; Pdx1-Cre) and Aldh7a1-/- mice. Conclusion: Inhibitions of ALDH7A1 and oxidative phosphorylation using gossypol and phenformin resulted in a regression of tumor formation in xenograft mice model and KPC mice model.
Bibliographical noteFunding Information:
This study was reviewed and approved by the Institutional Animal Care and Use Committee of the National Cancer Center Research Institute, which is an Association for the Assessment and Accreditation of Laboratory Animal Care International accredited facility that abides by the Institute of Laboratory Animal Resources guide (protocols: NCC-19-459, NCC-19-462, NCC-19-506, NCC-16-345, NCC-19-460). This research was supported by the National Cancer Center of Korea to SYK, HL, HJ (# 1910291, 1910292, 1910293, 2010271) and to SSH (#1710190).
© The author(s).
All Science Journal Classification (ASJC) codes
- Medicine (miscellaneous)
- Pharmacology, Toxicology and Pharmaceutics (miscellaneous)