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首页> 外文期刊>Oncogene >Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway
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Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway

机译：EGFR抑制剂和亚砷酸盐联合治疗人EGFR阳性黑色素瘤的细胞凋亡：PI3K-AKT途径的抑制作用

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Epidermal growth factor receptor (EGFR) is expressed, albeit at low or intermediate levels, in human melanomas at the different stages of tumor progression. Coexpression of EGFR with its ligand TGF indicates their role in paracrine and autocrine growth regulation of melanomas. As it was previously observed for several types of cancer, specific inhibitors of EGFR-mediated signaling may reduce antiapoptotic properties of cancer cells and sensitize them to cytotoxic drugs. We recently reported that arsenite, particularly in combination with inhibitors of the PI3K-AKT and mitogen-activated protein kinase (MAPK) kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways, induces high levels of apoptosis in different melanomas. Since EGFR signaling operates via activation of the PI3K-AKT and MEK-ERK pathways, we suggested that the combination of arsenite and EGFR inhibitors might also effectively induce apoptosis in melanoma. Here, we demonstrate that a moderate concentration of arsenite (5–10 M) indeed upregulates apoptosis induced by EGFR inhibitors in EGFR-positive melanomas. In contrast, induction of apoptosis in melanomas with negligible surface expression of EGFR or with defective EGFR signaling requires direct suppression of the PI3K-AKT and MAPK pathways by specific pharmacological inhibitors in the presence of arsenite. Under these conditions, metastatic melanoma cell lines undergo TNF-related apoptosis-inducing ligand (TRAIL)- and tumor necrosis factor alpha (TNF)-mediated apoptosis. Taken together, these data provide additional approaches in sensitizing melanomas to the cytotoxic effects of specific inhibitors of survival pathways.
机译：表皮生长因子受体（EGFR）在肿瘤发展的不同阶段在人黑素瘤中表达，尽管水平较低或中等。 EGFR及其配体TGF的共表达表明它们在黑色素瘤的旁分泌和自分泌生长调节中发挥作用。正如先前针对几种类型的癌症所观察到的那样，EGFR介导的信号传导的特异性抑制剂可能会降低癌细胞的抗凋亡特性并使它们对细胞毒性药物敏感。我们最近报道，亚砷酸盐，特别是与PI3K-AKT抑制剂和有丝分裂原激活的蛋白激酶（MAPK）激酶（MEK）-细胞外信号调节激酶（ERK）途径组合，可在不同的黑色素瘤中诱导高水平的细胞凋亡。由于EGFR信号传导通过PI3K-AKT和MEK-ERK途径的激活而起作用，因此我们建议亚砷酸盐和EGFR抑制剂的组合也可能有效诱导黑素瘤的凋亡。在这里，我们证明中等浓度的亚砷（5-10 M）确实上调了EGFR抑制剂在EGFR阳性黑色素瘤中诱导的凋亡。相反，在EGFR表面表达可忽略或EGFR信号缺陷的黑色素瘤中诱导凋亡需要在亚砷酸盐存在下通过特异性药理抑制剂直接抑制PI3K-AKT和MAPK途径。在这些条件下，转移性黑素瘤细胞系经历TNF相关凋亡诱导配体（TRAIL）和肿瘤坏死因子α（TNF）介导的凋亡。综上所述，这些数据提供了使黑色素瘤对生存途径的特定抑制剂的细胞毒性作用敏感的其他方法。

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