1. Academic Validation
  2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination

SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination

  • J Exp Clin Cancer Res. 2019 Feb 13;38(1):76. doi: 10.1186/s13046-019-1069-3.
Ce Li 1 Lutao Du 2 Yidan Ren 3 Xiaoyan Liu 4 Qinlian Jiao 3 Donghai Cui 4 Mingxin Wen 4 Chuanxin Wang 2 Guangwei Wei 4 Yunshan Wang 2 Aiguo Ji 5 Qin Wang 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
  • 2 Department of Clinical Laboratory, The Second Hospital of Shandong University, 247 Beiyuan Street, Tianqiao District, Jinan, 250033, Shandong, China.
  • 3 International Biotechnology R&D Center, Shandong University School of Ocean, 180 Wenhua Xi Road, Weihai, 264209, Shandong, China.
  • 4 Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China.
  • 5 School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China. [email protected].
  • 6 Department of Anesthesiology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, China. [email protected].
Abstract

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.

Keywords

Breast cancer; Cell apoptosis; DNA-damage response; PDCD4; Radiotherapy; SKP2.

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