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Suppression of fatty acid oxidation supports pancreatic cancer growth and survival under hypoxic conditions through autophagy induction

Cancer Gene Therapy volume 30, pages 878–889 (2023)Cite this article

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Abstract

Hypoxia, one of the key features of solid tumors, induces autophagy, which acts as an important adaptive mechanism for tumor progression under hypoxic environment. Cellular metabolic reprogramming has been correlated with hypoxia, but the molecular connection to the induction of autophagy remains obscure. Here, we show that suppression of fatty acid oxidation (FAO) by hypoxia induces autophagy in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for their growth and survival. Reduced cellular acetyl-CoA levels caused by FAO inhibition decreases LC3 acetylation, resulting in autophagosome formation. Importantly, PDAC cells are significantly dependent on this metabolic reprogramming, as improving FAO leads to a reduction in hypoxia-induced autophagy and an increase in cell death after chemotherapy. Thus, our study supports that suppression of FAO is an important metabolic response to hypoxia and indicates that targeting this pathway in PDAC may be an effective therapeutic approach.

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Fig. 1: PDAC cells reduce FAO upon hypoxia.
Fig. 2: FAO regulates autophagy in PDAC cells.
Fig. 3: FAO regulates autophagy through acetyl-CoA.
Fig. 4: FAO regulates LC3 acetylation.
Fig. 5: FAO regulates PDAC growth and drug resistance under hypoxia.
Fig. 6: FAO induction synergizes with chemotherapy to induce cell death of PDAC tumors.

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Data availability

Data generated in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (2019R1A2C1089937 and 2022R1F1A1066394).

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Authors and Affiliations

  1. Department of Biochemistry, Institute for Aging and Metabolic Diseases, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea

    Byungjoo Kim, Jihye Gwak, Minjoong Kim, Seungyeon Yang, Sunsook Hwang, Seungmin Shin & Seung Min Jeong

  2. Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, 05505, South Korea

    Ji Hye Kim & Jaekyoung Son

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BK, JG, MK, SY and SS: Investigation and formal analysis. SH and JHK: data analysis. JS: Review & Editing. SMJ: Conceptualization, Funding acquisition, Writing.

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Correspondence to Seung Min Jeong.

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Kim, B., Gwak, J., Kim, M. et al. Suppression of fatty acid oxidation supports pancreatic cancer growth and survival under hypoxic conditions through autophagy induction. Cancer Gene Ther 30, 878–889 (2023). https://doi.org/10.1038/s41417-023-00598-y

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