Nedd8-activating enzyme inhibitor MLN4924 (Pevonedistat), inhibits miR-1303 to suppress human breast cancer cell proliferation via targeting p27Kip1

  • Exp Cell Res. 2020 Jul 15;392(2):112038. doi: 10.1016/j.yexcr.2020.112038.
Yujiao Chen  1 ,  Mengge Du  1 ,  Shadamu Yusuying  2 ,  Wei Liu  1 ,  Yawen Tan  3 ,  Ping Xie  4
Affiliations
  • 1. Department of Cell Biology, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China.
  • 2. The First School of Clinical Medicine, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, 830011, China.
  • 3. Department of Breast and Thyroid Surgery, The Second People's Hospital of Shenzhen, Guangdong Province, 518035, China.
  • 4. Department of Cell Biology, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China. Electronic address: [email protected].
PMID: 32360865 DOI: 10.1016/j.yexcr.2020.112038
Abstract

MLN4924/Pevonedistat, a NEDD8-activating Enzyme (NAE, E1) inhibitor, has shown notable anti-cancer effect in pre-clinical trials, but it still faces tolerance resistance risk. Combination target therapy indicates a much better clinical effect than single target, and miRNAs are beneficial for easy detection in bodily fluids and tissues. Up to now, MLN4924 and miRNA-targeting combination approaching to treat breast Cancer patients remains largely unknown. Here, microRNA-seq analysis showed that the expression of miR-1303 was significantly decreased after MLN4924 treatment in breast Cancer cells. Moreover, miR-1303 was abnormally high in breast Cancer tissues, and breast Cancer patients with high miR-1303 showed poor prognosis. Functionally, excessive miR-1303 promoted the malignant phenotypes of breast Cancer cells. Excessive miR-1303 accelerated cell cycle progression by promoting G2/M arrest. Furthermore, we revealed that miR-1303 targeted p27Kip1 to release G2/M arrest. Notably, excessive miR-1303 partially disturbed the anti-cancer effect of MLN4924. These findings provide potential evidences for combined anti-cancer target therapy of breast Cancer patients in the future.

Keywords
Breast cancer; Combined drug therapy; MLN4924; miR-1303.
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