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SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis

Cell Death & Differentiation volume 30, pages 1916–1930 (2023)Cite this article

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Abstract

Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the role of SLC25A51 in human disease, such as cancer, remains undefined. Here, we report that SLC25A51 is upregulated in multiple cancers, which promotes cancer cells proliferation. Loss of SLC25A51 elevates the mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, leading to the impairment of P5CS enzymatic activity, which is the key enzyme in proline biogenesis, and the reduction in proline contents. Notably, we find fludarabine phosphate, an FDA-approved drug, is able to bind with and inhibit SLC25A51 functions, causing mitochondrial NAD+ decrease and proteins hyperacetylation, which could further synergize with aspirin to reinforce the anti-tumor efficacy. Our study reveals that SLC25A51 is an attractive anti-cancer target, and provides a novel drug combination of fludarabine phosphate with aspirin as a potential cancer therapy strategy.

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Fig. 1: SLC25A51 expression is elevated in multiple cancers and negatively associates with patients prognosis.
Fig. 2: SLC25A51 knockdown suppresses cancer cells proliferation in vivo and in vitro.
Fig. 3: SLC25A51 deficiency causes SIRT3 dysfunction and mitochondrial proteins hyper-acetylation.
Fig. 4: Hyper-acetylation impairs P5CS enzymatic activity induced by SLC25A51 knockdown.
Fig. 5: Proline replenishment counteracts the inhibitory effects of SLC25A51 deficiency.
Fig. 6: Fludarabine phosphate is screened as a potential SLC25A51 inhibitor.
Fig. 7: Aspirin synergizes with fludarabine phosphate to inhibit tumor growth.

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Data availability

The RNA-seq data was submitted to NCBI SRA database (BioProject ID: PRJNA953609). The full and uncropped western blots were uploaded as the Supplemental Material. Other datasets used and/or analyzed during the study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Zhanlong Shen (Peking University People’s Hospital), Xinshan Ye (Peking university), Xiaoyan Qiu (Peking University) and Jiadong Wang (Peking University) for providing us cell lines. We thank Yaxin Lou (Peking University) for the assistance of mass spectrometry analysis; Lihua An (Peking university) for the analysis of amino acids contents; Liping Liu (Shanghai Institute of Materia Medica) for the assistance of molecular docking; Qian Wang (Peking University) for the assistance of MST assay. This work was supported by grants from National Natural Science Foundation of China (82172959, 81874147 and 81671389).

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  1. These authors contributed equally: Yutong Li, Juntao Bie.

Authors and Affiliations

  1. Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, 100191, China

    Yutong Li, Juntao Bie, Chen Song, Tianzhuo Zhang, Meiting Li & Jianyuan Luo

  2. Department of Gastroenterological Surgery, Peking University People’s Hospital, Beijing, 100044, China

    Long Zhao & Changjiang Yang

  3. Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Jianyuan Luo

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YL, JB and JL designed the research. YL, JB and CS performed most of the experiments. TZ and ML assisted with the cell culture. LZ and CY collected the tumor samples.

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Correspondence to Jianyuan Luo.

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Li, Y., Bie, J., Zhao, L. et al. SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis. Cell Death Differ 30, 1916–1930 (2023). https://doi.org/10.1038/s41418-023-01185-2

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