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Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin

Oncogene volume 42, pages 2278–2293 (2023)Cite this article

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Abstract

Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.

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Fig. 1: DIOS inhibited the progression of ESCC.
Fig. 2: DIOS inhibited the CDK2/Rb/E2F2/RRM2 signaling pathway in ESCC cells.
Fig. 3: DIOS inhibited the proliferation and migration, and induced cell cycle arrest of ESCC by targeting CDK2.
Fig. 4: DIOS suppressed the growth of ESCC in vivo.
Fig. 5: The combination of DIOS and CDDP enhanced the anti-tumor effect in ESCC cells.
Fig. 6: The combination of DIOS and CDDP enhanced the anti-tumor effect in ESCC PDX model.
Fig. 7: Evaluation of drug toxicity and side effects of DIOS, CDDP alone and in combination in PDX model and HEK-293T cells.
Fig. 8: The combination of DIOS and CDDP reduced nephrotoxicity of CDDP.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81572972), the Supporting Plan of Scientific and Technological Innovation Team in Universities of Henan Province (20IRTSTHN029), the Scientific and Technological Research Project of Henan Province (212102310250).

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  1. These authors contributed equally: Yihuan Chen, Xiaoshuo Dai.

Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China

    Yihuan Chen, Xiaoshuo Dai, Wei Chen, Yan Qiao, Xiaoxuan Duan, Kai Zhang, Xinhuan Chen, Xin Li, Saijun Mo, Wenbo Cao, Xiang Li, Kangdong Liu, Ziming Dong & Jing Lu

  2. Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China

    Yan Qiao, Xinhuan Chen, Xin Li, Saijun Mo, Wenbo Cao, Xiang Li, Kangdong Liu, Ziming Dong & Jing Lu

  3. State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China

    Yan Qiao, Xinhuan Chen, Xin Li, Saijun Mo, Wenbo Cao, Xiang Li, Kangdong Liu, Ziming Dong & Jing Lu

  4. Department of Pathology, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan Province, 450003, PR China

    Ruihua Bai

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Contributions

YHC and JL contributed to the design of the experiments. YHC, XSD, and WC performed the experiments and analyzed the data. YQ, RHB, XXD, and KZ helped to perform the experiments and contributed to the software analysis. XHC, XL, SJM, WBC, XL, KDL, and ZMD performed material preparation and data analysis. YHC and XSD wrote the manuscript. JL revised the manuscript and supervised the study.

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Correspondence to Jing Lu.

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Chen, Y., Dai, X., Chen, W. et al. Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin. Oncogene 42, 2278–2293 (2023). https://doi.org/10.1038/s41388-023-02750-2

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