The Oncology Center of Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cancer Lett. 2010 Nov 1;297(1):117-25. doi: 10.1016/j.canlet.2010.05.004.
The purpose of this work is to study mechanisms underlying anti-tumor effects of farnesyltransferase inhibitors (FTIs) in non-small cell lung cancer (NSCLC). We demonstrate that mRNA and protein levels of Ras homologue enriched in brain (Rheb) are highly expressed both in NSCLC tissues and in NSCLC cell lines. Rheb expression levels correlate with phosphorylation of its downstream target S6 and the sensitivity of NSCLC cells to FTIs (R115777 and SCH66336)-induced growth inhibition and apoptosis. FTIs effectively and preferentially inhibited Rheb downstream signaling in NSCLC cells. Moreover, inhibition of Rheb functions by FTIs or dominant-negative Rheb mutants enhance the effects of cisplatin on NSCLC cells. Rheb-CSVL, a FTIs-resistant mutant, reduces the effects of FTIs on NSCLC cells. Our results suggest that Rheb is a critical target for FTIs therapy in NSCLC.
本工作旨在研究法尼基转移酶抑制剂（FTIs）在非小细胞肺癌（NSCLC）中抗肿瘤作用的机制。我们证明 Ras 同源物富含脑（Rheb）在 NSCLC 组织和 NSCLC 细胞系中均高度表达。Rheb 的表达水平与 S6 的下游靶标磷酸化及其对 NSCLC 细胞对 FTI（R115777 和 SCH66336）诱导的生长抑制和凋亡的敏感性相关。FTIs 能有效且优先地抑制 NSCLC 细胞中 Rheb 的下游信号。此外，FTIs 或显性负性 Rheb 突变体抑制 Rheb 功能增强了顺铂对 NSCLC 细胞的作用。FTIs 抗性突变体 Rheb-CSVL 降低了 FTI 对 NSCLC 细胞的作用。我们的结果表明，Rheb 是 NSCLC 中 FTI 治疗的关键靶标。
