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Platycodin D represses β-catenin to suppress metastasis of cetuximab-treated KRAS wild-type colorectal cancer cells

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Abstract

Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is extensively used for clinical therapy in KRAS wild-type colorectal cancer (CRC) patients. However, some patients still cannot get benefit from the therapy, because metastasis and resistance occur frequently after cetuximab treatment. New adjunctive therapy is urgently needed to suppress metastasis of cetuximab-treated CRC cells. In this study, we used two KRAS wild-type CRC cells, HT29 and CaCo2, to investigate whether platycodin D, a triterpenoid saponin isolated from Chinese medicinal herb Platycodon grandifloras, is able to suppress the metastasis of cetuximab-treated CRC. Label-free quantitative proteomics analyses showed that platycodin D but not cetuximab significantly inhibited expression of β-catenin in both CRC cells, and suggested that platycodin D counteracted the inhibition effect of cetuximab on cell adherence and functioned in repressing cell migration and invasion. Western blot results showed that single platycodin D treatment or combined platycodin D and cetuximab enhanced inhibition effects on expressions of key genes in Wnt/β-catenin signaling pathway, including β-catenin, c-Myc, Cyclin D1 and MMP-7, compared to single cetuximab treatment. Scratch wound-healing and transwell assays showed that platycodin D combined with cetuximab suppressed migration and invasion of CRC cells, respectively. Pulmonary metastasis model of HT29 and CaCo2 in nu/nu nude mice consistently showed that combined treatment using platycodin D and cetuximab inhibited metastasis significantly in vivo. Our findings provide a potential strategy to inhibit CRC metastasis during cetuximab therapy by addition of platycodin D.

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All data were supported in manuscript and supplementary materials.

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Acknowledgements

We thank Shanghai Bioprofile Technology Company, Ltd for providing technical help in label-free quantitative proteomics analyses.

Funding

This work was partially supported by the Natural Science Foundation of China Grant number 81972826 and 12174203.

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Author notes

  1. Yongming Lv and Wenhong Wang contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Tianjin Union Medical Center, Nankai University, Tianjin, China

    Yongming Lv, Wenhong Wang & Yijia Wang

  2. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Yanfei Liu, Ben Yi, Tianhao Chu & Zhiqiang Feng

  3. The Fourth Central Hospital Affiliated to Nankai University, Tianjin, China

    Jun Liu

  4. TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, China

    Xuehua Wan

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Contributions

Conceptualization, XW and YW; investigation, YL (Yongming Lv), WW, YL. (Yanfei Liu), BY, TC, ZF and JL; writing—original draft preparation, XW and YW; writing—review and editing, XW and YW All authors have read and agreed to the published version of the manuscript.

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Correspondence to Xuehua Wan or Yijia Wang.

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All animal experiments complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978) and was approved by the Ethics Committee of Tianjin Union Medical Center.

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Lv, Y., Wang, W., Liu, Y. et al. Platycodin D represses β-catenin to suppress metastasis of cetuximab-treated KRAS wild-type colorectal cancer cells. Clin Exp Metastasis 40, 339–356 (2023). https://doi.org/10.1007/s10585-023-10218-6

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