Artemether Inhibits Breast Cancer Cells Invasion Via Downregulating TNFα Of TAMs

Human breast cancer is still one of the intractable diseases worldly for its high incidence,high metastasis rate and comparatively poor prognosis.Within the microenvironment of breast cancer,stromal cells,particularly tumor-associated macrophages(TAMs),which have complicated sources,are of great importance during the progress of breast cancer.These so called TAMs support invasion and metastasis of cancer cells by the means of paracrine or direct contact.Therapy methods target the recruitment,polarization,activation and function of TAMs are in rapid development.Extensive researches have reveled that Artemisinin derivatives have other biological functions including anti-tumor,anti-inflammation and immune regulation apart from anti-malarial function.As one of Artemisinin derivatives,Artemether has been using as anti-malarial agent clinically.Though some researchers has reported anti-tumor function of Artemether in different tumors,it is still underestimated whether TAMs play vital roles in the anti-tumor function of Artemether.Therefore,our research explored anti-tumor effects of Artemether via TAMs both in vitro and in vivo.We discovered in vitro that Artemether has no effects on the proliferations,apoptosis and cell cycle of 4T1 and Raw264.7 in both state and co-culture conditions,but it does inhibits the invasion ability of 4T1 after co-culture with Raw264.7.We further discovered that Artemether inhibits TNFa secreated by TAMs in co-culture system.NF-kB,which has intimate association with the invasion ability of breast cancer cells after activation,is one of the important signal molecules in the downstream of TNFa.Our data further showed that Artemether blocks p65 to locate in nucleus and thus inhibits the activation of NF-kB.Furthermore,Artemether decreases the expression and activation of MMP2 and MMP9.We also found that Artemether retards the growth of implanted tumour with macrophage-dependent way and inhibits lung metastasis.Besides,we find Artemether decreases the expression of TNFa in peritoneal macrophages and decreases secreting level of tumor tissue.However,Artemether has complicated regulating effects on the phenotypes of macrophages.Taken together,we conclude that Artemether inhibits TNFa secreted by TAMs and thus blocks activation of NF-κB in 4T1 leading to the inhibition of invasion of 4T1 after co-culturing with Raw 264.7.Therefore,our research sheds light on the subsidiary therapy of breast cancer metastasis by Artemether via inhibiting TNFa secreted by TAMs.