Osteocyte-Derived GDF15 Promotes Paclitaxel Resistance, Tumor Growth, and Bone Microenvironment Regulation in...

With changes in lifestyle and dietary patterns, the incidence of prostate cancer in China has been increasing steadily, and it has become one of the most common malignancies in men. Chemotherapy remains a primary treatment for prostate cancer, but the subsequent development of drug resistance by tumor cells markedly compromises its therapeutic efficacy. Growth differentiation factor 15 (GDF15) has been shown to be closely associated with tumor cell proliferation and metastasis; however, its contribution to the drug resistance of prostate cancer cells within the tumor microenvironment has not been systematically investigated. In this study, we treated drug-resistant prostate cancer cells (PC3-TXR and DU145-TXR) with conditioned medium (CM) and examined GDF15 expression by Western blotting, real-time PCR, and ELISA. We then exposed drug-resistant cells to various concentrations of recombinant GDF15 (rGDF15) and CM, and assessed invasive and metastatic abilities as well as sensitivity to paclitaxel using Transwell and CCK-8 assays. We generated GDF15-knockout osteocytes using CRISPR-Cas9 technology and detected the expression of resistance-related signaling pathway components and epithelial-mesenchymal transition (EMT) markers. These findings were further validated through subcutaneous tumor formation assays in mice combined with immunohistochemistry to explore the mechanism by which GDF15 regulates drug resistance and metastasis in the crosstalk between drug-resistant prostate cancer cells and bone cells. Our results revealed that GDF15 expression was significantly upregulated in both drug-resistant prostate cancer cells and their surrounding microenvironment. rGDF15 enhanced the invasion and drug resistance of resistant cells, whereas knockout of GDF15 effectively inhibited these effects. Furthermore, we demonstrated that GDF15 regulates the biological behavior of drug-resistant cells by targeting and modulating the AKT signaling pathway and by promoting EMT initiation and progression. These findings clarify the molecular pathway through which GDF15 governs drug resistance in prostate cancer cells, offering a new direction for the treatment of tumor metastasis and biologically targeted therapy.