Overall survival of pancreatic ductal adenocarcinoma is doubled by Aldh7a1 deletion in the KPC mouse

Theranostics. 2021 Jan 19;11(7):3472-3488. doi: 10.7150/thno.53935. eCollection 2021.

Abstract

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.

Keywords: ALDH7A1; KPC mice model; cancer metabolism; oxidative phosphorylation complex I; pancreatic ductal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / deficiency
  • Aldehyde Dehydrogenase / genetics*
  • Aldehydes / metabolism
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic
  • Gossypol / pharmacology
  • Homeodomain Proteins / genetics*
  • Humans
  • Lipid Peroxidation / drug effects
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Oxidative Phosphorylation / drug effects
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Phenformin / pharmacology
  • Proto-Oncogene Proteins p21(ras) / deficiency
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction
  • Survival Analysis
  • Trans-Activators / deficiency
  • Trans-Activators / genetics*
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • Aldehydes
  • Homeodomain Proteins
  • Trans-Activators
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • pancreatic and duodenal homeobox 1 protein
  • Phenformin
  • Aldehyde Dehydrogenase
  • Aldh7a1 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Gossypol