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PPDPF-mediated regulation of BCAA metabolism enhances mTORC1 activity and drives cholangiocarcinoma progression

Oncogene volume 44, pages 1415–1433 (2025) Cite this article

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Abstract

Tumor cells display profound changes in the metabolism of branched-chain amino acids (BCAA). However, how these changes are regulated to facilitate tumorigenesis is not yet completely understood. Here, we identified pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a BCAA-responsive protein through extensive screening using stable isotope labeling with amino acids in cell culture (SILAC). PPDPF is upregulated in cholangiocarcinoma to enhance the malignant phenotype of cholangiocarcinoma cells by activating the mTORC1 signaling pathway. Metabolic flux analysis and mechanistic studies revealed that PPDPF prevented the interaction between MCCA and MCCB, thus inhibiting leucine catabolism and activating mTORC1 signaling. Moreover, upon amino acid starvation, ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2) and OTU deubiquitinase 4 (OTUD4) cooperatively regulated the stability of the PPDPF protein by modulating its ubiquitination. Additionally, monocytes/macrophage-derived IL-10 increased the BCAA content in cholangiocarcinoma cells and stabilized the PPDPF protein, even under amino acid starvation conditions. Knockout of PPDPF or restriction of leucine intake significantly inhibits the progression of cholangiocarcinoma in a mouse model. Collectively, we discovered a novel role for PPDPF in promoting the progression of cholangiocarcinoma by activating mTORC1 signaling through the inhibition of leucine catabolism. The present study suggests that targeting PPDPF or decreasing dietary leucine intake may provide a new strategy to improve the treatment efficacy of cholangiocarcinoma.

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Fig. 1: PPDPF is highly expressed in cholangiocarcinoma and promotes the malignant phenotype of cholangiocarcinoma cells.
The alternative text for this image may have been generated using AI.
Fig. 2: Knockdown of PPDPF in Cholangiocarcinoma Reduced BCAAs and Inhibited mTORC1 Signaling.
The alternative text for this image may have been generated using AI.
Fig. 3: PPDPF is located in the mitochondria, interacts with MCCA, and suppresses BCAA catabolism.
The alternative text for this image may have been generated using AI.
Fig. 4: The level of PPDPF protein decreases upon amino acid deficiency.
The alternative text for this image may have been generated using AI.
Fig. 5: ARIH2 and OTUD4 regulate PPDPF protein levels.
The alternative text for this image may have been generated using AI.
Fig. 6: IL-10 increases PPDPF protein levels.
The alternative text for this image may have been generated using AI.
Fig. 7: Knocking down PPDPF or restricting dietary leucine intake can inhibit CCA progression.
The alternative text for this image may have been generated using AI.

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Data availability

Our RNA sequencing data can be downloaded from the NCBI GEO database under the accession number GSE244424 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE244424). All other data supporting the findings of this study are available from the corresponding author upon reasonable request.

Materials availability

Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, YZD (728002719@shsmu.edu.cn).

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Acknowledgements

This work was supported by National Natural Science Foundation of China 82030087, 82172980, 82372846, 82302918, 82060308, 82173116, 82103675, 82302978, 82302318 and 82273077; Fund 2021JJ30039 from Hunan Provincial Science and Technology Department; Fund 2024JJ6701 from the Natural Science Foundation of Hunan Province of China; Fund GZC20233169 from Postdoctoral Fellowship Program of CPSF; fund 23ZR1458700 from Science and Technology Commission of Shanghai Municipality; National Key Laboratory of Respiratory Diseases (SKLRD-OP-202208); the High level project of People’s Hospital of Yangjiang (G2021001); Guizhou Provincial Science and Technology Projects GCC[2022]037-1 and funding from Ministry of Human Resources and Social Security of the People’s Republic of China. We also acknowledged the support of the talent base program from the Guizhou Talent Office and Dr. Li Changjie (Shanghai JFKR Organoid Biotechnology Co., Ltd) for the technical assistance.

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Author notes

  1. These authors contributed equally: Zhi Li, Yidi Guan.

Authors and Affiliations

  1. Key Laboratory of Molecular Radiation Oncology (Xiangya Hospital, Central South University), Changsha, China

    Zhi Li, Yidi Guan, Jie Gao, Haiping Pei, Zhuoxian Rong & Lunquan Sun

  2. Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, China

    Zhi Li & Lunquan Sun

  3. Institute of Cancer Research, National Clinical Research Center for Geriatric Disorders (Xiangya), Xiangya Hospital, Central South University, Changsha, China

    Zhi Li & Lunquan Sun

  4. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Yidi Guan

  5. Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jie Gao, Zimei Zeng, Qi Fan & Yuezhen Deng

  6. NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People’s Hospital, Guiyang, China

    Lan Zhu, Qianyu Jing & Quan Wan

  7. Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China

    Xinxin Ren

  8. Department of General Surgery, Zhongshan Xuhui Hospital Affiliated to Fudan University, Shanghai, China

    Dexiang Zhang

  9. The Department of Emergency Surgery, the Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Yefei Rong

  10. Department of Oncology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China

    Junju He & Bin Xu

  11. Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yuefang Zhang

  12. Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China

    Nan Li

  13. Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Pan Chen

  14. Department of Research, the University of HongKong-Shenzhen Hospital, Shenzhen, China

    Yingjie Nie

  15. Yangjiang Key Laboratory of Respiratory Disease, People’s Hospital of Yangjiang, 529500, Yangjiang, Guangdong, China

    Yuezhen Deng

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  1. Zhi Li
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Contributions

ZL and YDG performed the major experiments and data analysis. YZD, YJN, BX, and LQS designed the experiments, performed the data analysis, and provided the project comments. N.L. provided the cholangiocarcinoma patients’ samples. JJH, HPP, DXZ, YFR, PC, and YFZ assisted in preparing the mouse model. JG, ZMZ, LZ, QYJ, QW, QF, XXR, and ZXR assisted with the experiments and provided technical help. YZD, ZL, and YDG were involved in manuscript preparation.

Corresponding authors

Correspondence to Lunquan Sun, Bin Xu, Yingjie Nie or Yuezhen Deng.

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The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. Cholangiocarcinoma samples were collected from the Shanghai Eastern Hepatobiliary Surgery Hospital (Shanghai, China) after informed consent was obtained from the patients. Ethical approval was obtained from the Institutional Ethics Committee of the hospital (S2018-114-02). Animal experiments were approved by the Animal Ethics Committee of Central South University (E2018-04).

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Li, Z., Guan, Y., Gao, J. et al. PPDPF-mediated regulation of BCAA metabolism enhances mTORC1 activity and drives cholangiocarcinoma progression. Oncogene 44, 1415–1433 (2025). https://doi.org/10.1038/s41388-025-03320-4

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