背景:前列腺癌(PCa)的发病率和死亡率正在上升。我们之前的研究表明,淫羊藿苷(ICA)和curcumol(CUR)的联合诱导PCa细胞的自噬和铁凋亡,和改变脂质代谢。我们旨在进一步探讨ICA和CUR的组合对肠道微生物群的影响,新陈代谢,和PCa的免疫力。
方法:建立小鼠皮下RM-1细胞肿瘤模型。进行16SrRNA测序以检测粪便肠道微生物群的变化。老鼠粪便中的SCFA,以及ICA-CUR对T细胞免疫的影响,检查IGFBP2和DNMT1。采用粪便微生物移植(FMT)技术探讨ICA-CUR的作用机制。将Si-IGFBP2和si/oe-DNMT1转染到RM-1和DU145细胞中,用ICA-CUR处理细胞以研究ICA-CUR对PCa发育的作用机制。
结果:ICA-CUR治疗后,肿瘤体积和重量都有所减少,伴随着肠道微生物群的变化。ICA-CUR影响SCFAs和DNMT1/IGFBP2/EGFR/STAT3/PD-L1通路。ICA-CUR增加CD3+CD8+IFN-γ的阳性率,CD3+CD8+Ki67细胞,以及血清中IFN-γ和IFN-α的水平。在FMT(与ICA-CUR组的捐赠者一起)之后,肿瘤体积和重量均减少。SCFAs增进肿瘤的发展和IGFBP2的表达。体外,DNMT1/IGFBP2促进细胞迁移和增殖。ICA-CUR抑制DNMT1/IGFBP2的表达。
结论:ICA-CUR介导肠道菌群与DNMT1/IGFBP2轴之间的相互作用,通过调节免疫反应和代谢来抑制PCa的进展,提示PCa的潜在治疗策略。
BACKGROUND: Prostate cancer (PCa) incidence and mortality rates are rising. Our previous research has shown that the combination of icariin (ICA) and curcumol (CUR) induced autophagy and ferroptosis in PCa cells, and altered lipid metabolism. We aimed to further explore the effects of the combination of ICA and CUR on gut microbiota, metabolism, and immunity in PCa.
METHODS: A mouse subcutaneous RM-1 cell tumor model was established. 16 S rRNA sequencing was performed to detect changes in fecal gut microbiota. SCFAs in mouse feces, and the effect of ICA-CUR on T-cell immunity, IGFBP2, and DNMT1 were examined. Fecal microbiota transplantation (FMT) was conducted to explore the mechanism of ICA-CUR. Si-IGFBP2 and si/oe-DNMT1 were transfected into RM-1 and DU145 cells, and the cells were treated with ICA-CUR to investigate the mechanism of ICA-CUR on PCa development.
RESULTS: After treatment with ICA-CUR, there was a decrease in tumor volume and weight, accompanied by changes in gut microbiota. ICA-CUR affected SCFAs and DNMT1/IGFBP2/EGFR/STAT3/PD-L1 pathway. ICA-CUR increased the positive rates of CD3+CD8+IFN-γ, CD3+CD8+Ki67 cells, and the levels of IFN-γ and IFN-α in the serum. After FMT (with donors from the ICA-CUR group), tumor volume and weight were decreased. SCFAs promote tumor development and the expression of IGFBP2. In vitro, DNMT1/IGFBP2 promotes cell migration and proliferation. ICA-CUR inhibits the expression of DNMT1/IGFBP2.
CONCLUSIONS: ICA-CUR mediates the interaction between gut microbiota and the DNMT1/IGFBP2 axis to inhibit the progression of PCa by regulating immune response and metabolism, suggesting a potential therapeutic strategy for PCa.