Li Ruiqian, Wu Hongyi, Ran Fengming, He Yixuan, Sun Hong, Peng Wenjun, Wang Qilin, Li Jun
Department of Urology, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China.
Pathology Department, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China.
Mol Immunol. 2025 Sep;185:27-38. doi: 10.1016/j.molimm.2025.07.006. Epub 2025 Jul 16.
Drug resistance in cancer treatment is a major challenge, and macrophage polarization plays a key role in the development of prostate cancer (PCa). Growth differentiation factor 15 (GDF15) is highly expressed in most cancers and is induced during anticancer treatment. The aim of this study was to investigate the regulatory mechanism of GDF15 in macrophage polarization and resistance to docetaxel (DTX) in PCa patients. We collected clinical samples from PCa patients to evaluate the expression level of GDF15 and its correlation with M2-type macrophage polarization. In this study, CCK-8, RTqPCR, flow cytometry and western blotting were used to investigate the mechanisms by which GDF15 regulates macrophage M2 polarization and PCa chemotherapy resistance. The results showed that GDF15 was significantly upregulated in PCa samples and was closely related to the level of M2 macrophage polarization. Further experiments revealed that M2 macrophages synthesize GDF15, which is involved in the regulation of DTX resistance in PCa cells. Following knockdown of GDF15 expression in M2-type macrophages, we observed that the resistance of PCa cells to DTX was significantly attenuated. This regulatory mechanism was achieved mainly through the inhibition of the PI3K/AKT signaling pathway, preventing the M2 polarization of macrophages. In conclusion, the upregulation of GDF15 in M2 macrophages can activate the PI3K/AKT signaling pathway, enhancing the DTX resistance of PCa cells. These findings provide new insights and potential targets for treatment strategies against PCa chemotherapy resistance.
癌症治疗中的耐药性是一个重大挑战，巨噬细胞极化在前列腺癌（PCa）的发展中起关键作用。生长分化因子15（GDF15）在大多数癌症中高度表达，并在抗癌治疗期间被诱导。本研究的目的是探讨GDF15在巨噬细胞极化以及PCa患者对多西他赛（DTX）耐药中的调控机制。我们收集了PCa患者的临床样本，以评估GDF15的表达水平及其与M2型巨噬细胞极化的相关性。在本研究中，采用CCK-8、RTqPCR、流式细胞术和蛋白质印迹法来研究GDF15调节巨噬细胞M2极化和PCa化疗耐药的机制。结果表明，GDF15在PCa样本中显著上调，且与M2巨噬细胞极化水平密切相关。进一步实验表明，M2巨噬细胞合成GDF15，其参与调节PCa细胞对DTX的耐药性。在敲低M2型巨噬细胞中GDF15的表达后，我们观察到PCa细胞对DTX的耐药性显著减弱。这种调控机制主要是通过抑制PI3K/AKT信号通路，阻止巨噬细胞的M2极化来实现的。总之，M2巨噬细胞中GDF15的上调可激活PI3K/AKT信号通路，增强PCa细胞对DTX的耐药性。这些发现为针对PCa化疗耐药的治疗策略提供了新的见解和潜在靶点。
