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Polysaccharides from Lentinus edodes prevent acquired drug resistance to docetaxel in prostate cancer cells by decreasing the TGF-β1 secretion of cancer-associated fibroblasts

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Abstract

Prostate cancer is one of the most prevalent lethal diseases among men globally. In the treatment of prostate cancer, the limited therapeutic efficacy of the standard non-hormonal systemic therapy docetaxel (DTX) represents an important challenge. Cancer-associated fibroblasts (CAFs) play a crucial role in resistance to therapy because of their prevalence and functional pleiotropy in tumor environments. Our previous research revealed that MPSSS, a novel polysaccharide extracted from Lentinus edodes, could significantly attenuate the immunosuppressive function of myeloid suppressor cells and CAFs. In this study, we investigated whether MPSSS could potentiate the efficacy of DTX against prostate cancer by inhibiting CAF-induced chemoresistance and elucidated its underlying mechanisms. The sensitivity of PC-3 prostate cancer cells cultured with conditioned medium derived from CAFs (CAF-CM) to DTX was assessed. The resistance effect induced by CAF-CM was abolished when CAFs were pretreated with MPSSS. Bioinformatic analysis of datasets from the Gene Expression Omnibus database revealed the activation of the transforming growth factor β1 (TGF-β1) signaling pathway in DTX-resistant cells. Based on this finding, we demonstrated that treatment with the TGF-β1 receptor inhibitor SB525334 reversed DTX resistance in CAFs, suggesting that TGF-β1 secreted by CAFs was a crucial intermediary in the development of DTX resistance in PC3 cells. Further research revealed that MPSSS decreases the secretion of TGF-β1 by inhibiting the JAK2/STAT3 pathway via Toll-like receptor 4 in CAFs. Overall, MPSSS might be a potential adjuvant treatment for DTX resistance in prostate cancer.

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Acknowledgements

The authors thank Miss Shuoshuo Ma for her advice and encouragement, and thank Prof. Qinghong Meng for her advice in writing, and thank Dr. Joe Barber Jr. from Edanz for editing the English text of a draft of this manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (31370910).

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Authors and Affiliations

  1. Chinese PLA medical school, Beijing, China

    Wensheng Zhang & Li Bai

  2. Department of Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China

    Wensheng Zhang & Li Bai

  3. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Ning Tao

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  1. Wensheng Zhang
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LB, NT, and WZ designed the research. WZ and LB revised and submitted the manuscript. WZ and NT performed the experiments, and LB analyzed the data.

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Correspondence to Ning Tao or Li Bai.

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Zhang, W., Tao, N. & Bai, L. Polysaccharides from Lentinus edodes prevent acquired drug resistance to docetaxel in prostate cancer cells by decreasing the TGF-β1 secretion of cancer-associated fibroblasts. J Nat Med 77, 817–828 (2023). https://doi.org/10.1007/s11418-023-01722-w

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