Song Kwon-Ho, Woo Seon Rang, Chung Joon-Yong, Lee Hyo-Jung, Oh Se Jin, Hong Soon-Oh, Shim Jaegal, Kim Yong Nyun, Rho Seung Bae, Hong Seung-Mo, Cho Hanbyoul, Hibi Masahiko, Bae Dong-Jun, Kim Sang-Yeob, Kim Min Gyu, Kim Tae Woo, Bae Young-Ki
Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Department of Biochemistry, Korea University College of Medicine, Seoul, Republic of Korea.
Cell Death Dis. 2017 Jan 5;8(1):e2536. doi: 10.1038/cddis.2016.462.
Rab escort protein 1 (REP1) is a component of Rab geranyl-geranyl transferase 2 complex. Mutations in REP1 cause a disease called choroideremia (CHM), which is an X-linked eye disease. Although it is postulated that REP1 has functions in cell survival or death of various tissues in addition to the eye, how REP1 functions in normal and cancer cells remains to be elucidated. Here, we demonstrated that REP1 is required for the survival of intestinal cells in addition to eyes or a variety of cells in zebrafish, and also has important roles in tumorigenesis. Notably, REP1 is highly expressed in colon cancer tissues and cell lines, and silencing of REP1 sensitizes colon cancer cells to serum starvation- and 5-FU-induced apoptosis. In an effort to elucidate the molecular mechanisms underlying REP1-mediated cell survival under those stress conditions, we identified FOXO3 as a binding partner of REP1 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that REP1 blocked the nuclear trans-localization of FOXO3 through physically interacting with FOXO3, thereby suppressing FOXO3-mediated apoptosis. Importantly, the inhibition of REP1 combined with 5-FU treatment could lead to significant retarded tumor growth in a xenograft tumor model of human cancer cells. Thus, our results suggest that REP1 could be a new therapeutic target in combination treatment for colon cancer patients.
Rab护送蛋白1（REP1）是Rab香叶基香叶基转移酶2复合物的一个组成部分。REP1的突变会导致一种名为脉络膜视网膜病变（CHM）的疾病，这是一种X连锁眼病。尽管据推测REP1除了在眼睛中，在各种组织的细胞存活或死亡中也具有功能，但REP1在正常细胞和癌细胞中的功能仍有待阐明。在此，我们证明REP1除了对眼睛或斑马鱼中的多种细胞之外，对肠道细胞的存活也是必需的，并且在肿瘤发生中也具有重要作用。值得注意的是，REP1在结肠癌组织和细胞系中高度表达，沉默REP1会使结肠癌细胞对血清饥饿和5-氟尿嘧啶诱导的凋亡敏感。为了阐明在这些应激条件下REP1介导细胞存活的分子机制，我们使用酵母双杂交（Y2H）分析系统鉴定出FOXO3是REP1的结合伴侣，并证明REP1通过与FOXO3物理相互作用来阻止FOXO3的核转位，从而抑制FOXO3介导的凋亡。重要的是，在人癌细胞异种移植肿瘤模型中，抑制REP1并联合5-氟尿嘧啶治疗可导致肿瘤生长显著减缓。因此，我们的结果表明REP1可能是结肠癌患者联合治疗中的一个新的治疗靶点。
