Resistin, a fat-derived secretory factor, promotes metastasis of MDA-MB-231 human breast cancer cells through ERM activation

Resistin, an adipocyte-secreted factor, is known to be elevated in breast cancer patients. However, the molecular mechanism by which resistin acts is not fully understood. The aim of this study was to investigate whether resistin could stimulate invasion and migration of breast cancer cells. Here, we report that resistin stimulated invasion and migration of breast cancer cells as well as phosphorylation of c-Src. Inhibition of c-Src blocked resistin-induced breast cancer cell invasion. Resistin increased intracellular calcium concentration, and chelation of intracellular calcium blocked resistin-mediated activation of Src. Resistin also induced phosphorylation of protein phosphatase 2A (PP2A). Inhibition of c-Src blocked resistin-mediated PP2A phosphorylation. In addition, resistin increased phosphorylation of PKC alpha. Inhibition of PP2A enhanced resistin-induced PKC alpha phosphorylation, demonstrating that PP2A activity is critical for PKC alpha phosphorylation. Resistin also increased phosphorylation of ezrin, radixin, and moesin (ERM). Additionally, ezrin interacted with PKC alpha, and resistin promoted colocalization of ezrin and PKC alpha. Either inhibition of c-Src and PKCa or knock-down of ezrin blocked resistin-induced breast cancer cells invasion. Moreover, resistin increased expression of vimentin, a key molecule for cancer cell invasion. Knock-down of ezrin abrogated resistin-induced vimentin expression. These results suggest that resistin play as a critical regulator of breast cancer metastasis.