Lee Jung Ok, Kim Nami, Lee Hye Jeong, Lee Yong Woo, Kim Su Jin, Park Sun Hwa, Kim Hyeon Soo
Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
Sci Rep. 2016 Jan 5;6:18923. doi: 10.1038/srep18923.
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 PKCα. Inhibition of PP2A enhanced resistin-induced PKCα phosphorylation, demonstrating that PP2A activity is critical for PKCα phosphorylation. Resistin also increased phosphorylation of ezrin, radixin, and moesin (ERM). Additionally, ezrin interacted with PKCα, and resistin promoted co-localization of ezrin and PKCα. Either inhibition of c-Src and PKCα 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.
抵抗素是一种脂肪细胞分泌因子，已知在乳腺癌患者中水平升高。然而，抵抗素发挥作用的分子机制尚未完全明确。本研究旨在探讨抵抗素是否能刺激乳腺癌细胞的侵袭和迁移。在此，我们报告抵抗素可刺激乳腺癌细胞的侵袭和迁移以及c-Src的磷酸化。抑制c-Src可阻断抵抗素诱导的乳腺癌细胞侵袭。抵抗素增加细胞内钙浓度，细胞内钙螯合可阻断抵抗素介导的Src激活。抵抗素还诱导蛋白磷酸酶2A（PP2A）的磷酸化。抑制c-Src可阻断抵抗素介导的PP2A磷酸化。此外，抵抗素增加蛋白激酶Cα（PKCα）的磷酸化。抑制PP2A增强抵抗素诱导的PKCα磷酸化，表明PP2A活性对PKCα磷酸化至关重要。抵抗素还增加埃兹蛋白、根蛋白和膜突蛋白（ERM）的磷酸化。此外，埃兹蛋白与PKCα相互作用，抵抗素促进埃兹蛋白和PKCα的共定位。抑制c-Src和PKCα或敲低埃兹蛋白均可阻断抵抗素诱导的乳腺癌细胞侵袭。此外，抵抗素增加波形蛋白的表达，波形蛋白是癌细胞侵袭的关键分子。敲低埃兹蛋白可消除抵抗素诱导的波形蛋白表达。这些结果表明抵抗素是乳腺癌转移的关键调节因子。
