Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway
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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DOI：
10.1038/sj.onc.1208125
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发表时间：
2005-01-20
期刊：
影响因子：
8
通讯作者：
Hei, TK
中科院分区：
文献类型：
--
作者：
Ivanov, VN;Hei, TK
表皮生长因子受体(EGFR)在肿瘤进展的不同阶段的人类黑色素瘤中有表达，尽管表达水平较低或中等。EGFR及其配体TGFα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。正如以前在几种类型的癌症中观察到的那样，EGFR介导的信号转导的特定抑制剂可能会降低癌细胞的抗凋亡特性，并使它们对细胞毒药物敏感。我们最近报道，亚砷酸盐，特别是与PI3K-AKT和丝裂原活化蛋白激酶(MEK)-细胞外信号调节激酶(ERK)途径的抑制剂联合使用，可以诱导不同类型黑色素瘤的高水平细胞凋亡。由于EGFR信号通路是通过激活PI3K-AKT和MEK-ERK通路发挥作用的，因此我们认为亚砷酸盐和EGFR抑制剂联合使用也可能有效地诱导黑色素瘤细胞的凋亡。在这里，我们证明了适度浓度的亚砷酸盐(5-10微米)确实上调了由EGFR抑制剂诱导的EGFR阳性黑色素瘤的细胞凋亡。相反，在EGFR表面表达可忽略的黑色素瘤或EGFR信号缺陷的黑色素瘤中，诱导细胞凋亡需要在亚砷酸盐存在下用特定的药物抑制剂直接抑制PI3K-AKT和MAPK通路。在这些条件下，转移性黑色素瘤细胞株经历了肿瘤坏死因子相关的凋亡诱导配体(TRAIL)和肿瘤坏死因子α(TNFpha)介导的凋亡。综上所述，这些数据提供了额外的方法，使黑色素瘤对特定的生存途径抑制物的细胞毒性作用敏感。
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 TGFalpha 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-AKTand 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 muM) 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-AKTand 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 (TNFalpha)- mediated apoptosis. Taken together, these data provide additional approaches in sensitizing melanomas to the cytotoxic effects of specific inhibitors of survival pathways.