Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: a new potential therapy for the treatment of melanoma.
Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: a new potential therapy for the treatment of melanoma.
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DOI：
10.1016/j.yexcr.2010.04.014
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发表时间：
2010-07-15
影响因子：
3.7
通讯作者：
Ivanov VN
中科院分区：
文献类型：
--
作者：
Karasic TB;Hei TK;Ivanov VN
癌细胞对凋亡的抵抗依赖于多种遗传和表观遗传机制的平衡，这些机制上调存活生长因子受体信号通路的效力，抑制死亡受体信号通路。胰岛素样生长因子-1受体（Insulin-like Growth Factor-1 Receptor, IGF-1R）信号通路在转移性黑色素瘤细胞中高度活跃，通过介导PI3K-AKT和MAPK通路的下游激活，控制一般细胞的存活和增殖。在本研究中，我们使用了具有确定基因型的人类黑色素瘤系，这些基因型代表了癌症发展的不同阶段：放射生长期WM35、垂直生长期WM793、转移性LU1205和WM9。所有这些线都有正常的NRAS。WM35、WM793、LU1205和WM9细胞发生BRAF （V600E）突变。WM35、WM9细胞PTEN表达正常，WM793细胞PTEN表达下调；最后，在LU1205细胞中，PTEN因突变而失活。Cyclolignan picropodophylin （PPP）是一种IGF-1R激酶活性的特异性抑制剂，在WM9和WM793细胞中强烈下调AKT活性的基础水平，在LU1205中适度下调，但对早期缺乏IGF-1R的WM35细胞中的AKT活性没有影响。此外，PPP在所有基因系中部分下调了活性ERK1/2的基础水平，这突出了另一种非braf通路在MAPK激活中的作用。PPP治疗的最终结果是诱导WM793、WM9和LU1205黑色素瘤细胞凋亡。另一方面，PPP在相对较窄的剂量范围内（近500 nM）对IGF-1R激酶活性的剂量依赖性抑制对黑色素瘤细胞和正常细胞的影响不同，诱导癌细胞凋亡和成纤维细胞的G2/M阻滞。为了进一步增强PPP对黑色素瘤细胞的促凋亡作用，我们采用tnf相关凋亡诱导配体（TRAIL）和PPP联合治疗。该组合显著增加了WM793和WM9细胞的凋亡死亡，但对AKT基础活性非常高的LU1205细胞只有轻微的增加。这一研究方向的最终目标是发现一种治疗高度耐药的人类转移性黑色素瘤的新方法。我们的发现为进一步对这种新疗法进行临床前评估提供了依据。
Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for WM793 and WM9 cells, but did so only modestly for LU1205 cells with very high basal activity of AKT. The ultimate goal of this direction of research is the discovery of a new treatment method for highly resistant human metastatic melanomas. Our findings provide the rationale for further preclinical evaluation of this novel treatment.
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胰岛素样生长因子I受体活性对于卡波西肉瘤的生长和生存至关重要。
影响因子：
8.8
作者：
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通讯作者：
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4.8
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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