标题：SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination
作者：Li, Ce; Du, Lutao; Ren, Yidan; Liu, Xiaoyan; Jiao, Qinlian; Cui, Donghai; Wen, Mingxin; Wang, Chuanxin; Wei, Guangwei; Wang, Yunshan 更多 作者机构：[Li, Ce; Ji, Aiguo] Shandong Univ, Sch Pharmaceut Sci, 44 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China.; [Du, Lutao; Wang, Chuanxin; Wang, 更多
通讯作者：Ji, AG;Wang, Q
通讯作者地址：[Ji, AG]Shandong Univ, Sch Pharmaceut Sci, 44 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China;[Wang, Q]Shandong Univ, Qilu Hosp, Dept Anesthesio 更多
来源：JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
关键词：Breast cancer; SKP2; PDCD4; Cell apoptosis; DNA-damage response;; Radiotherapy
摘要：Background: S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear.; Methods: To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor.; Results: We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo.; Conclusions: We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.