황선숙 (가톨릭대학교 의과대학)

한빛사논문

조회601

황선숙Sunsook Hwang

가톨릭대학교 의과대학

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Adv. Sci., Dec 25 2023, | https://doi.org/10.1002/advs.202304702 Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance

Sunsook Hwang¹, Seungyeon Yang ¹, Kyungsoo Park ^2,3, Byungjoo Kim ¹, Minjoong Kim ¹, Seungmin Shin ¹, Ahyoung Yoo ⁴, Jiyun Ahn ^4,5, Juneil Jang ², Yeong Shin Yim ², Rho H Seong³, Seung Min Jeong ¹

¹Department 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.

²Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

³School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, 08826, South Korea.

⁴Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, South Korea.

⁵Division of Food Biotechnology, University of Science and Technology, Daejeon, 34113, South Korea.

CORRESPONDING AUTHOR : Seung Min Jeong

Abstract

The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-27)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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