The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways
The farnesyltransferase inhibitor R115777 (ZARNESTRA®) enhances the pro-apoptotic activity of interferon-α through the inhibition of multiple survival pathways
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DOI：
10.1002/ijc.22964
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发表时间：
2007-11-15
影响因子：
6.4
通讯作者：
Tagliaferri, Pierosandro
中科院分区：
文献类型：
--
作者：
Caraglia, Michele;Marra, Monica;Tagliaferri, Pierosandro
干扰素α诱导EGF-RAS->；Raf-1->；ERK依赖的生存通路，对抗细胞因子诱导的细胞凋亡。本文评价了法尼基转移酶抑制剂(FTI)R115777与干扰素α联合应用对肿瘤细胞的生长抑制和细胞凋亡的影响。同时暴露于R115777和干扰素α可产生抗增殖和促凋亡的协同作用。在本实验条件下，干扰素α和R115777可完全拮抗干扰素α诱导的RAS和ERK-1/2活性的升高，并显著降低Akt活性。此外，R115777联合干扰素α方案治疗可延缓已建立的KB细胞裸鼠移植瘤的生长，而单用药几乎无效。R115777在体内也能拮抗干扰素α诱导的RAS依赖的生存通路。RAF-1是RAS的下游靶点之一，已有报道通过Bad的置换和/或磷酸化来激活bcl2。我们发现干扰素α诱导的Raf-1的线粒体定位可被R115777拮抗。此外，干扰素α促进Raf-1/bcl2免疫结合形成和细胞内共定位，并促进Bad在Ser 112的磷酸化，R115777再次抵消了这些作用。此外，使用编码显性阴性或显性阳性Raf-1的质粒会分别拮抗和增强Raf-1和BCL2之间的免疫共沉淀。总之，FTI R115777通过抑制依赖于ras等细胞内蛋白异戊二烯基化的不同生存途径，在体外和体内都极大地增强了IFNA的抗肿瘤活性。(C)2007年Wiley-Liss，Inc.
interferon a (IFN alpha) induces an EGF-Ras -> Raf-1 -> Erk dependent survival pathway counteracting apoptosis induced by the cytokine. In this paper we have evaluated the effects of the combination between farnesyl-transferase inhibitor (FTI) R115777 and IFN alpha on the growth inhibition and apoptosis of cancer cells. Simultaneous exposure to R115777 and IFN alpha produced synergistic both antiproliferative and proapoptotic effects. In these experimental conditions, IFN alpha and R115777 completely antagonized the increased activity of both Ras and Erk-1/2 induced by IFN alpha and strongly reduced Akt activity. Furthermore, treatment with R115777 in combination with IFN alpha regimen induced tumor growth delay on established KB cell xenografts in nude mice, while the single agents were almost inactive. R115777 was again able to antagonize the Ras-dependent survival pathway induced by IFN alpha also in vivo. Raf-1, one of the downstream targets of Ras, has been reported to activate bcl-2 through displacement and/or phosphorylation of Bad. We have found that IFN alpha induced mitochondrial localization of Raf-1 that was antagonized by R115777. Moreover, IFN alpha increased Raf-1/bcl-2 immuno-conjugate formation and intracellular co-localization and enhanced phosphorylation of Bad at Ser 112 and again R115777 counteracted all these effects. Moreover, the use of plasmids encoding for dominant negative or dominant positive Raf-1 antagonized and potentiated, respectively, the co-immunoprecipitation between Raf-1 and bcl2. In conclusion, FTI R115777 strongly potentiates the antitumor activity of IFNa both in vitro and in vivo through the inhibition of different survival pathways that are dependent from isoprenylation of intracellular proteins such as ras. (c) 2007 Wiley-Liss, Inc.