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首页> 外文期刊>Molecular and Cellular Biology >Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth
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Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth

机译：Geranylgeranyltransferase I抑制剂靶向RalB抑制锚定依赖性生长并诱导凋亡，而RalA抑制锚定依赖性生长。

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Geranylgeranyltransferase I inhibitors (GGTIs) are presently undergoing advanced preclinical studies and have been shown to disrupt oncogenic and tumor survival pathways, to inhibit anchorage-dependent and -independent growth, and to induce apoptosis. However, the geranylgeranylated proteins that are targeted by GGTIs to induce these effects are not known. Here we provide evidence that the Ras-like small GTPases RalA and RalB are exclusively geranylgeranylated and that inhibition of their geranylgeranylation mediates, at least in part, the effects of GGTIs on anchorage-dependent and -independent growth and tumor apoptosis. To this end, we have created the corresponding carboxyl-terminal mutants that are exclusively farnesylated and verified that they retain the subcellular localization and signaling activities of the wild-type geranylgeranylated proteins and that Ral GTPases do not undergo alternative prenylation in response to GGTI treatment. By expressing farnesylated, GGTI-resistant RalA and RalB in Cos7 cells and human pancreatic MiaPaCa2 cancer cells followed by GGTI-2417 treatment, we demonstrated that farnesylated RalB, but not RalA, confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of GGTI-2417. Conversely, farnesylated RalA but not RalB expression renders MiaPaCa2 cells less sensitive to inhibition of anchorage-independent growth. Furthermore, farnesylated RalB, but not RalA, inhibits the ability of GGTI-2417 to suppress survivin and induce p27Kip1 protein levels. We conclude that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition.
机译：目前，Geranylgeranyltransferase I抑制剂（GGTIs）正在进行高级临床前研究，并已证明它们可以破坏致癌和肿瘤存活途径，抑制锚定依赖性和非依赖性生长，并诱导凋亡。但是，由GGTI靶向诱导这些作用的香叶基香叶基化蛋白尚不清楚。在这里，我们提供的证据表明，像Ras一样的小GTP酶RalA和RalB仅被香叶基香叶基化，并且抑制它们的香叶基香叶基化至少或部分介导了GGTI对锚定依赖性和非依赖性生长以及肿瘤细胞凋亡的影响。为此，我们创建了仅被法尼基化的相应羧基末端突变体，并验证了它们保留了野生型香叶基香叶基化蛋白的亚细胞定位和信号传导活性，并且Ral GTPases不会响应GGTI处理而经历其他异戊烯化作用。通过在Cos7细胞和人胰腺MiaPaCa2癌细胞中表达法呢基化，抗GGTI的RalA和RalB，然后进行GGTI-2417处理，我们证明了法呢基化的RalB而非RalA赋予了对凋亡的和抗锚定的生长依赖性的抗性GGTI-2417。相反，法尼基化的RalA而不是RalB的表达使MiaPaCa2细胞对抑制锚定非依赖性生长的敏感性降低。此外，法尼基化的RalB抑制GGTI-2417抑制survivin并诱导p27 Kip1 蛋白质水平的能力，但不抑制RalA。我们得出结论，RalA和RalB是GGTI介导的肿瘤细胞凋亡和生长抑制的重要，功能上不同的靶标。

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