Lee Ji-Yeon, Kim Hyun-Ji, Rho Seung Bae, Lee Seung-Hoon
Department of Life Science, YongIn University, Samga-dong Chuingu, Yonginsi, Korea.
Research Institute, National Cancer Center, Ilsandong-gu, Goyang-si Gyeonggi-do, Korea.
Oncotarget. 2016 Apr 5;7(14):18541-57. doi: 10.18632/oncotarget.8105.
Clusterin is a secretory heterodimeric glycoprotein and the overexpression of secretory clusterin (sCLU) promotes cancer cell proliferation and reduces chemosensitivity. Therefore, sCLU might be an effective target for anticancer therapy. In the current study, we identified eIF3f as a novel CLU-interacting protein and demonstrated its novel function as a CLU inhibitor. The overexpression of eIF3f retarded cancer cell growth significantly and induced apoptosis. In addition, eIF3f interacted with the α-chain (1-227) of sCLU. This interaction blocked modification of psCLU, thereby decreasing the expression and secretion of α/β CLU. Consequently, the overexpression of eIF3f suppressed Akt and ERK signaling and subsequently depleted CLU expression. In addition, eIF3F stabilized p53, which increased the expression of p21 and Bax. Interestingly, the expression of Bax was increased without the activation of p53. eIF3f injected into a xenograft model of human cervical cancer in nude mice markedly inhibited tumor growth. The identification of this novel function of eIF3f as a sCLU inhibitor might open novel avenues for developing improved strategies for CLU-targeted anti-cancer therapies.
聚集素是一种分泌型异源二聚体糖蛋白，分泌型聚集素（sCLU）的过表达促进癌细胞增殖并降低化疗敏感性。因此，sCLU可能是抗癌治疗的有效靶点。在本研究中，我们鉴定出真核翻译起始因子3f（eIF3f）是一种新的与CLU相互作用的蛋白，并证明了其作为CLU抑制剂的新功能。eIF3f的过表达显著抑制癌细胞生长并诱导细胞凋亡。此外，eIF3f与sCLU的α链（1 - 227）相互作用。这种相互作用阻断了psCLU的修饰，从而降低了α/β CLU的表达和分泌。因此，eIF3f的过表达抑制了Akt和ERK信号通路，随后降低了CLU的表达。此外，eIF3F使p53稳定，这增加了p21和Bax的表达。有趣的是，在未激活p53的情况下Bax的表达也增加了。将eIF3f注射到裸鼠人宫颈癌异种移植模型中可显著抑制肿瘤生长。eIF3f作为sCLU抑制剂这一新功能的鉴定可能为开发改进的CLU靶向抗癌治疗策略开辟新途径。
