成纤维细胞生长因子-2通过一个涉及蛋白激酶Cε、B-Raf和S6K2的复合体保护小细胞肺癌细胞免于凋亡。

FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2.

作者信息

Pardo Olivier E, Wellbrock Claudia, Khanzada Umme K, Aubert Muriel, Arozarena Imanol, Davidson Sally, Bowen Frances, Parker Peter J, Filonenko V V, Gout Ivan T, Sebire Neil, Marais Richard, Downward Julian, Seckl Michael J

机构信息

Lung Cancer Biology Group, Cancer Research UK, Imperial College London, Hammersmith Hospitals Campus, Du Cane Road, London, UK.

出版信息

EMBO J. 2006 Jul 12;25(13):3078-88. doi: 10.1038/sj.emboj.7601198. Epub 2006 Jun 29.

DOI:10.1038/sj.emboj.7601198

PMID:16810323

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1500980/

Abstract

Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X(L), and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCepsilon or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCepsilon increases XIAP and Bcl-X(L) levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X(L) and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling.

摘要

小细胞肺癌（SCLC）患者死于化疗耐药。成纤维细胞生长因子-2（FGF-2）可增加抗凋亡蛋白XIAP和Bcl-X（L）的表达，并引发SCLC细胞的化疗耐药。在此我们表明，这些效应是通过形成一种由B-Raf、PKCε和S6K2组成的特定多蛋白复合物介导的。S6K1、Raf-1和其他PKC亚型不会形成类似的复合物。RNA干扰介导的B-Raf、PKCε或S6K2下调可消除FGF-2介导的细胞存活。相反，PKCε的过表达可增加SCLC细胞中XIAP和Bcl-X（L）的水平以及化疗耐药性。在四环素诱导系统中，增加的S6K2激酶活性可触发XIAP、Bcl-X（L）的上调和促存活效应。然而，增加的S6K1激酶活性则没有这种作用。因此，介导促存活/化疗耐药信号传导的是S6K2而非S6K1。