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  3. APC/C-regulated CPT1C promotes tumor progression by upregulating the energy supply and accelerating the G1/S transition

APC/C-regulated CPT1C promotes tumor progression by upregulating the energy supply and accelerating the G1/S transition

  • Cell Commun Signal. 2024 May 23;22(1):283. doi: 10.1186/s12964-024-01657-z.
Huihui Zhao # 1,  Xinxin Cheng # 1,  Liping Yan # 2,  Fang Mi 3,  Wenqing Wang 1,  Yuying Hu 1,  Xingyang Liu 1,  Yuyan Fan 1,  Qingjie Min 1,  Yan Wang 1 4,  Weimin Zhang 1,  Qingnan Wu 5 6,  Qimin Zhan 7 8 9 10
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 2 Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 3 State Key Laboratory of Molecular Oncology, National Cancer center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 4 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 5 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China. wuqingnan@bjmu.edu.cn.
  • 6 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China. wuqingnan@bjmu.edu.cn.
  • 7 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China. zhanqimin@bjmu.edu.cn.
  • 8 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China. zhanqimin@bjmu.edu.cn.
  • 9 Peking University International Cancer Institute, Beijing, 100142, China. zhanqimin@bjmu.edu.cn.
  • 10 Soochow University Cancer Institute, Suzhou, 215000, China. zhanqimin@bjmu.edu.cn.
  • # Contributed equally.
PMID: 38783346 DOI: 10.1186/s12964-024-01657-z
Abstract

Background: In addition to functioning as a precise monitoring mechanism in cell cycle, the anaphase-promoting complex/cyclosome (APC/C) is reported to be involved in regulating multiple metabolic processes by facilitating the ubiquitin-mediated degradation of key Enzymes. Fatty acid oxidation is a metabolic pathway utilized by tumor cells that is crucial for malignant progression; however, its association with APC/C remains to be explored.

Methods: Cell cycle synchronization, immunoblotting, and propidium iodide staining were performed to investigate the carnitine palmitoyltransferase 1 C (CPT1C) expression manner. Proximity ligation assay and co-immunoprecipitation were performed to detect interactions between CPT1C and APC/C. Flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium, inner salt (MTS) assays, cell-scratch assays, and transwell assays and xenograft transplantation assays were performed to investigate the role of CPT1C in tumor progression in vitro and in vivo. Immunohistochemistry was performed on tumor tissue microarray to evaluate the expression levels of CPT1C and explore its potential clinical value.

Results: We identified CPT1C as a novel APC/C substrate. CPT1C protein levels exhibited cell cycle-dependent fluctuations, peaking at the G1/S boundary. Elevated CPT1C accelerated the G1/S transition, facilitating tumor cell proliferation in vitro and in vivo. Furthermore, CPT1C enhanced fatty acid utilization, upregulated ATP levels, and decreased Reactive Oxygen Species levels, thereby favoring cell survival in a harsh metabolic environment. Clinically, high CPT1C expression correlated with poor survival in patients with esophageal squamous cell carcinoma.

Conclusions: Overall, our results revealed a novel interplay between fatty acid utilization and cell cycle machinery in tumor cells. Additionally, CPT1C promoted tumor cell proliferation and survival by augmenting cellular ATP levels and preserving redox homeostasis, particularly under metabolic stress. Therefore, CPT1C could be an independent prognostic indicator in esophageal squamous cell carcinoma.

Keywords

APC/C; CPT1C; Cell cycle; Fatty acid utilization; Tumor progression.

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