Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling.
Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling.
复制标题
Gas6/Axl 轴通过 Akt/GSK-3 β/β-连环蛋白信号传导促进乳腺癌化疗耐药和转移
作者：
Wang C;Jin H;Wang N;Fan S;Wang Y;Zhang Y;Wei L;Tao X;Gu D;Zhao F;Fang J;Yao M;Qin W
乳腺癌的化疗耐药性在过去的研究中一直受到极大的关注。然而，针对化疗耐药细胞的合理治疗策略的发展仍然是临床肿瘤学的一个挑战。通过整合敏感亲本细胞（MCF-7）和阿霉素耐药细胞（MCF-7/ADR）之间基因表达和磷酸化受体酪氨酸激酶的全局差异的数据，我们将Axl鉴定为多药耐药乳腺癌细胞中化疗耐药性和转移的潜在靶点。我们分析了Axl在57个乳腺癌细胞系中的表达，并检测到其在间充质乳腺癌细胞系中的表达水平显著增加。Axl沉默抑制化疗耐药乳腺癌细胞的侵袭和转移潜力，以及当与多柔比星组合时增加癌细胞的消除。此外，在临床前测定中，Axl抑制剂R428显示在多柔比星处理后增加的细胞死亡。此外，使用基于磷酸激酶阵列的蛋白质组学分析，我们确定Akt/GSK-3 β/β-catenin级联负责Axl诱导的细胞侵袭。β-catenin的核转位然后诱导ZEB1的转录上调，这反过来又调节乳腺癌细胞中的DNA损伤修复和阿霉素抗性。最重要的是，Axl与肿瘤样本中的下游靶点相关，并与乳腺癌患者的不良预后相关。这些结果表明，Gas6/Axl轴赋予乳腺癌的侵袭性，并可能代表化疗耐药性和转移的治疗靶点。
Chemoresistance in breast cancer has been of great interest in past studies. However, the development of rational therapeutic strategies targeting chemoresistant cells is still a challenge in clinical oncology. By integrating data from global differences of gene expression and phospho-receptor tyrosine kinases between sensitive parental cells (MCF-7) and doxorubicin-resistant cells (MCF-7/ADR), we identified Axl as a potential target for chemoresistance and metastasis in multidrug resistant breast cancer cells. We analyzed Axl expression in 57 breast cancer cell lines and detected a dramatic increase in its expression level in mesenchymal breast cancer cell lines. Axl silencing suppressed invasive and metastatic potentials of chemoresistant breast cancer cells as well as increased elimination of cancer cells when combined with doxorubicin. Furthermore, in preclinical assays, an Axl inhibitor R428 showed increased cell death upon doxorubicin treatment. Additionally, using phospho-kinase array based proteomic analysis, we identified that Akt/GSK-3β/β-catenin cascade was responsible for Axl-induced cell invasion. Nuclear translocation of β-catenin then induced transcriptional upregulation of ZEB1, which in turn regulated DNA damage repair and doxorubicin-resistance in breast cancer cells. Most importantly, Axl was correlated with its downstream targets in tumor samples and was associated with poor prognosis in breast cancer patients. These results demonstrate that Gas6/Axl axis confers aggressiveness in breast cancer and may represent a therapeutic target for chemoresistance and metastasis.