Nuclear Localization of Fibroblast Growth Factor Receptor 1 in Breast Cancer Cells Interacting with Cancer Associated Fibroblasts

IF 2.5 Q3 ONCOLOGY
Jinyoung Suh, Do-Hee Kim, Su-jung Kim, N. Cho, Yeon-Hwa Lee, Jeong-Hoon Jang, Y. Surh
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引用次数: 2

Abstract

Cancer-associated fibroblasts (CAFs) represent a major component of the tumor microenvironment and interplay with cancer cells by secreting cytokines, growth factors and extracellular matrix proteins. When estrogen receptor-negative breast cancer MDA-MB-231 cells were treated with the CAF-conditioned medium (CAF-CM), Akt and STAT3 involved in cell proliferation and survival were activated through phosphorylation. CAFs secrete fibroblast growth factor 2 (FGF2), thereby stimulating breast cancer cell progression. Akt activation induced by CAF-CM in MDA-MB-231 cells was abolished when FGF2-neutralizing antibody was added. Treatment of MDA-MB-231 cells directly with FGF2 enhanced the phosphorylation of Akt and the FGF receptor (FGFR) substrate, FRS2α. These events were abrogated by siRNA-mediated silencing of FGFR1. In a xenograft mouse model, co-injection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced activation of Akt. Stable knockdown of FGFR1 blunted Akt phosphorylation in xenograft tumors. MDA-MB-231 cells co-cultured with CAFs or directly stimulated with FGF2 exhibited enhanced nuclear localization of FGFR1. Notably, FGF2 stimulation produced reactive oxygen species (ROS) accumulation in MDA-MB-231 cells, and FGF2-induced nuclear accumulation of FGFR1 was abrogated by the ROS scavenging agent, N-acetylcysteine.
乳腺癌细胞中成纤维细胞生长因子受体1与癌症相关成纤维细胞相互作用的核定位
癌症相关成纤维细胞(CAFs)是肿瘤微环境的主要组成部分,通过分泌细胞因子、生长因子和细胞外基质蛋白与癌细胞相互作用。当雌激素受体阴性的乳腺癌MDA-MB-231细胞用ca - cm处理时,参与细胞增殖和存活的Akt和STAT3通过磷酸化被激活。CAFs分泌成纤维细胞生长因子2 (FGF2),从而刺激乳腺癌细胞的进展。加入fgf2中和抗体后,ca - cm诱导的MDA-MB-231细胞中Akt活化被消除。用FGF2直接处理MDA-MB-231细胞可增强Akt和FGF受体(FGFR)底物FRS2α的磷酸化。sirna介导的FGFR1沉默消除了这些事件。在异种移植小鼠模型中,MDA-MB-231细胞与表达FGF2的活化成纤维细胞共同注射可显著增强Akt的活化。FGFR1的稳定下调可减弱异种移植物肿瘤中Akt的磷酸化。与CAFs共培养或直接用FGF2刺激的MDA-MB-231细胞显示出FGFR1的核定位增强。值得注意的是,FGF2刺激在MDA-MB-231细胞中产生活性氧(ROS)积累,而FGF2诱导的FGFR1核积累被ROS清除剂n -乙酰半胱氨酸消除。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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