The Mechanism Of Kadsurenone In The Treatment Of Breast Cancer Bone Metastasis

Bone metastasis is a deleterious and debilitating aspect of BC patients.Up to 70% of BC patients who succumb to disease present with bone metastases on autopsy.Bone metastases lesions are primarily osteolytic since BC cells could regulate the bone-tumor microenvironment.Osteoclasts were over activated by BC cells while BC cells were reversely promoted by cytokines released from bone matrix degradation.Current treatment strategies for BC bone metastases mainly focused on breaking such “vicious osteolytic cycle”.The great majority of BC produces osteolytic bone metastases.This process is characterized by over activated osteoclastogenesis and subsequent bone destruction.BC cells could form a complex and multigenic programed “vicious osteolytic cycle” to remold the bone microenvironment and promote cancer progression after,or even before,bone colonization.Cytokines secreted by BC cells like IL-6,PTHRP and TNF? could stimulate osteoblasts and up-regulate the RANKL/OPG ratio,which further stimulates the development of osteoclasts from myeloid precursors.At the same time,other cytokines such as IL-11 and OPN could directly promote ostoclastogenesis.Activated osteoclasts degrade the bone matrix,and release TGF?,BMPs and IGFs,which are mainly stored in bone matrix,reversely stimulate BC progression.The expression of PAF and its receptor PTAFR in BC cell lines have also been demonstrated.In the tumor microenvironment,PAF is secreted and accumulated by infiltrated inflammation cells and tumor cells per se,which forms an autocrine loop.PTAFR is a G-protein coupled receptor(GPCR).PAF/PTAFR activation resulted complex cell responses including increase of cell motility,up-regulation of IL-6 and MMP expression,and activation of NF-?B signaling.The increased migration ability is an important characteristic for cancer cells forming metastatic lesions,including bone metastases.Both of published literatures and our results revealed increased cell migration ability of BC cells after PAF treatment.To avoid the harmful effects of PAF,mostly PAF inhibitors are used to abolish or attenuate the PAF/PTAFR signaling activation.Bioinformatics analysis provided clues that the PAF/PTAFR signaling pathway may play important roles in regulating BC bone metastasis and osteoclastogenesis.In the current study,we demonstrated that PAF could promote BC cell migration and induce BMMs differentiation.Kadsurenone could attenuate both processes,and could be considered as a potential therapeutic reagent for BC bone metastases.Comparing to the “vicious osteolytic cycle”,PAF could promote BMMs differentiate into osteoclasts by two parallel manners.On one hand,PAF could stimulate BC cells up-regulate downstream signaling such as IL-6,IL-11,MMPs and NF-?B,which further activate osteoclastogenesis.On the other hand,PAF could also directly activate BMMs differentiate into osteoclasts.In the current study,we demonstrated that Kadsurenone could inhibit both the BC induced or PAF directly stimulated osteoclastogenesis.Expression of osteoclast differentiation markers are all down-regulated after Kadsurenone treatment.The process mainly due to the inhibition of NF-?B activation.In conclusion,we have demonstrated that Kadsurenone could effectively attenuate BC formed osteolytic bone metastases by blocking the PAF/PTAFR signaling.