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Lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy

Abstract

Gliomas are the most common primary tumors of the central nervous system, with approximately half of patients presenting with the most aggressive form of glioblastoma. Although several molecular markers for glioma have been identified, they are not sufficient to predict the prognosis due to the extensive genetic heterogeneity within glioma. Our study reveals that the ratio of IMPDH1 to IMPDH2 expression levels serves as a molecular indicator for glioma treatment prognosis. Patients with a higher IMPDH1/IMPDH2 ratio exhibit a worse prognosis, while those with a lower ratio display a more favorable prognosis. We further demonstrate that IMPDH1 plays a crucial role in maintaining cellular GTP/GDP levels following DNA damage compared to IMPDH2. In the absence of IMPDH1, cells experience an imbalance in the GTP/GDP ratio, impairing DNA damage repair capabilities and rendering them more sensitive to TMZ. This study not only introduces a novel prognostic indicator for glioma clinical diagnosis but also offers innovative insights for precise and stratified glioma treatment.

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Fig. 1: Glioma patients with a high ratio of IMPDH1 to IMPDH2 expression levels have a worse prognosis.
Fig. 2: Cells with a high ratio of IMPDH1 to IMPDH2 expression levels are insensitive to TMZ.
Fig. 3: IMPDH1 and IMPDH2 differ in their enzymatic activities in response to DNA damage.
Fig. 4: DNA damage repair pathway is downregulated in IMPDH1 deficient cells.
Fig. 5: IMPDH1 deficient cells have reduced DNA damage repair ability.

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Acknowledgements

The authors are grateful to members of the Wang laboratory for insightful discussions and technical assistance.

Funding

The authors thank the following for funding support: the National Key R&D Program of China (2022YFA1302800), the National Science Fund for Distinguished Young Scholars (82125031), and the National Natural Science Foundation of China (82230089).

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RXY was responsible for designing and performing the experiments. RXY contributed to writing the original draft. XYD was responsible for bioinformatics analysis. XYD, LXM, YEC provided feedback on the report. RXY, XYD, LXM and WJD reviewed and edited the manuscript.

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Correspondence to Xiaoman Li, Ence Yang or Jiadong Wang.

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Ruan, X., Xiong, Y., Li, X. et al. Lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy. Cancer Gene Ther 31, 1081–1089 (2024). https://doi.org/10.1038/s41417-024-00793-5

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