Repression of BCL2 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells
Repression of BCL2 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells
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DOI：
10.1158/0008-5472.can-07-0776
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Sonenshein, Gail E.
中科院分区：
文献类型：
--
作者：
Wu, Min;Min, Chengyin;Sonenshein, Gail E.
编码赖氨酸氧化酶（LOX）的基因被鉴定为ras精确基因（rrg），具有恢复ras介导的NIH 3T3成纤维细胞转化的能力。在25%的肺癌和85%的胰腺癌中发现了类似的RAS基因突变。在微阵列分析中，发现这些癌症显示LOX基因表达降低。因此，LOX基因抑制这些癌细胞转化表型的能力得到了测试。LOX是作为50 kda分泌前体Pro-LOX合成的，该前体被加工成32 kda的活性酶（LOX）和18 kda的前肽（LOX- pp）。最近，我们在ras转化的NIH 3T3细胞中绘制了Pro-LOX与LOX-PP的rrg活性。异位Pro-LOX和LOX-PP在H1299肺癌细胞中的表达抑制了软琼脂的生长和Matrigel中侵入性集落的形成，降低了细胞外信号调节激酶（ERK）和Akt的激活，其中LOX-PP的活性明显提高。同样，在PANC-1胰腺癌细胞中表达LOX-PP可有效降低ERK和Akt活性，抑制软琼脂细胞的生长和迁移能力。核因子- κ B （nf - κ B）及其靶基因BCL2在70%至75%的胰腺癌中过表达，最近被认为与侵袭性表型有关。LOX-PP显著降低NF-kappa B和Bcl-2水平。将Bcl-2重新引入表达LOX-PP的PANC-1或H1299细胞中，可以恢复转化后的表型，这表明Bcl-2是一个重要的靶点。因此，LOX-PP能有效抑制肺癌和胰腺癌细胞的侵袭性表型，提示其在这些癌症的治疗中具有潜在的应用价值。
The gene encoding lysyl oxidase (LOX) was identified as the ras recision gene (rrg), with the ability to revert Ras-mediated transformation of NIH 3T3 fibroblasts. Mutations in RAS genes have been found in similar to 25% of lung cancers and in 85% of pancreatic cancers. In microarray analysis, these cancers were found to display reduced LOX gene expression. Thus, the ability of the LOX gene to repress the transformed phenotype of these cancer cells was tested. LOX is synthesized as a 50-kDa secreted precursor Pro-LOX that is processed to the 32-kDa active enzyme (LOX) and to an 18-kDa propeptide (LOX-PP). Recently, we mapped the rrg activity of Pro-LOX to the LOX-PP in Ras-transformed NIH 3T3 cells. Ectopic Pro-LOX and LOX- PP expression in H1299 lung cancer cells inhibited growth in soft agar and invasive colony formation in Matrigel and reduced activation of extracellular signal-regulated kinase (ERK) and Akt, with LOX-PP showing substantially higher activity. Similarly, LOX-PP expression in PANC-1 pancreatic cancer cells effectively reduced ERK and Akt activity and inhibited growth in soft agar and ability of these cells to migrate. Nuclear Factor-kappa B (NF-kappa B) and its target gene BCL2, which are overexpressed in 70% to 75% of pancreatic cancers, have recently been implicated in invasive phenotype. LOX-PP substantially reduced NF-kappa B and Bcl-2 levels. Reintroduction of Bcl-2 into PANC-1 or H1299 cells expressing LOX-PP restored the transformed phenotype, suggesting that Bcl-2 is an essential target. Thus, LOX-PP potently inhibits invasive phenotype of lung and pancreatic cancer cells, suggesting potential therapeutic applications in treatment of these cancers.