2. Academic Validation
  3. Redistribution of defective mitochondria-mediated dihydroorotate dehydrogenase imparts 5-fluorouracil resistance in colorectal cancer

Redistribution of defective mitochondria-mediated dihydroorotate dehydrogenase imparts 5-fluorouracil resistance in colorectal cancer

  • Redox Biol. 2024 May 23:73:103207. doi: 10.1016/j.redox.2024.103207.
Shuohui Dong 1,  Mingguang Zhang 2,  Zhiqiang Cheng 1,  Xiang Zhang 1,  Weili Liang 1,  Songhan Li 3,  Linchuan Li 4,  Qian Xu 4,  Siyi Song 4,  Zitian Liu 1,  Guangwei Yang 1,  Xiang Zhao 1,  Ze Tao 1,  Shuo Liang 5,  Kexin Wang 6,  Guangyong Zhang 7,  Sanyuan Hu 8
Affiliations

Affiliations

  • 1 Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhua Xilu, Jinan, Shandong, 250012, China.
  • 2 Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 3 Department of General Surgery, Peking University People's Hospital, Beijing, 100044, China.
  • 4 Department of General Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, 250014, China.
  • 5 Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, No. 4, Duanxing West Road, Jinan, Shandong,250022, China. Electronic address: shuoliang_sdent@163.com.
  • 6 Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhua Xilu, Jinan, Shandong, 250012, China. Electronic address: wkx3726@163.com.
  • 7 Department of General Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, 250014, China. Electronic address: guangyongzhang@hotmail.com.
  • 8 Department of General Surgery, Qilu Hospital of Shandong University, No. 107 Wenhua Xilu, Jinan, Shandong, 250012, China. Electronic address: drsanyuanhu@163.com.
PMID: 38805974 DOI: 10.1016/j.redox.2024.103207
Abstract

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal Cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant Cancer cells; however, potential therapeutic targets remain elusive. This study investigated Ferroptosis vulnerability and Dihydroorotate Dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against Ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that Ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.

Keywords

Chemoresistance; Colorectal cancer; Dihydroorotate dehydrogenase; Ferroptosis; Lipid metabolic reprogramming.

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