Polydatin ameliorates low-density lipoprotein cholesterol and lipid metabolism by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in triple-negative breast cancer with hyperlipidemia

To investigate polydatin's effects on low-density lipoprotein cholesterol (LDL-C) and lipid metabolism in mice with triple-negative breast cancer (TNBC) and hyperlipidemia, as well as the underlying mechanism of proprotein convertase subtilisin/kexin type 9 (PCSK9). In vivo, we designed two animal models, namely breast pad in situ inoculation of TNBC model and TNBC with lung metastatic were inoculated with the caudal vein model. Mice were administered a high-fat diet. Upon the completion of the experiment, plasma triglycerides (TG), total plasma cholesterol (TC), plasma LDL-C, and plasma high-density lipoprotein cholesterol (HDL-C) were measured. ELISA was employed to measure PCSK9 and the low-density lipoprotein receptor (LDLR). The morphological alterations were observed using Oil-red O staining. Immunohistochemical labeling was used to determine the expression of PCSK9 and LDLR in mouse breast cancer (BC) tissues. MTT, wound healing assay, and the transwell migration and invasion test were conducted to examine co-cultured adipocytes' effects on the growth, invasion, and migration of BC cells. In the 4T1-luc cell model injected in situ into the breast pad and 4T1-luc cell model injected into the tail vein, we observed that a high-fat diet promoted the proliferation and lung metastasis of BC cells, whereas polydatin suppressed the proliferation and lung metastasis of BC cells. Co-culture of BC cells with adipocytes enhanced the proliferation, invasion, and metastasis, while polydatin intervention inhibited the growth, invasion, and metastasis. After treatment with polydatin, serum lipid levels decreased, PCSK9 decreased, LDLR increased, and LDL-C decreased in mouse BC, liver, and lung tissues. After polydatin treatment, PCSK9 decreased, LDLR increased, and LDL-C decreased in an in vitro co-culture system of BC cells and adipocytes. After transfection of siRNA PCSK9 in the co-culture system, the LDLR increased more significantly, and the LDL-C decreased more significantly. After transfection of LV-PCSK9, PCSK9 decreased, LDLR increased, and LDL-C decreased. We concluded that polydatin inhibited breast tumor proliferation and distant lung metastasis in mice promoted by a high lipid environment. By suppressing PCSK9, polydatin alters the lipid profile of hyperlipidemic TNBC mice and prevents distant metastases. Our findings provide credence to the established practice of using polydatin in treating TNBC combined with hyperlipidemia.