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Theranostics 2021; 11(7):3472-3488. doi:10.7150/thno.53935 This issue Cite

Research Paper

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

Jae-Seon Lee^1,2*, Ho Lee^3*, Sang Myung Woo^3,4,5, Hyonchol Jang¹, Yoon Jeon¹, Hee Yeon Kim¹, Jaewhan Song², Woo Jin Lee⁵, Eun Kyung Hong⁶, Sang-Jae Park⁷, Sung-Sik Han^7✉, Soo-Youl Kim^1✉

1. Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
2. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
3. Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
4. Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
5. Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea.
6. Department of Pathology, National Cancer Center, Goyang, Republic of Korea.
7. Department of Surgery, Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea.
*These authors contributed equally to this work.

✉ Corresponding authors: E-mail: kimsooyoulcom (S.-Y.K.); sshanre.kr (S.-S.H.).

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 (Kras^G12D; Trp53^R172H; 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: cancer metabolism, pancreatic ductal adenocarcinoma, ALDH7A1, oxidative phosphorylation complex I, KPC mice model

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