Suppression of Musashi‑2 by the small compound largazole exerts inhibitory effects on malignant cells

Int J Oncol. 2020 May;56(5):1274-1283. doi: 10.3892/ijo.2020.4993. Epub 2020 Feb 19.

Abstract

RNA‑binding protein Musashi‑2 (MSI2) serves as a regulator of numerous pivotal biological processes associated with cancer initiation, development and resistance to treatment, and may represent a promising drug target. However, whether MSI2 inhibition is of value in antitumor treatment remains to be determined. The present study demonstrated that MSI2 was upregulated in non‑small cell lung cancer (NSCLC) and was inversely associated with the clinical outcome of the patients. Molecular docking analysis demonstrated that the small compound largazole binds to and may be a potential inhibitor of MSI2. Largazole markedly decreased the protein and mRNA levels of MSI2 and suppressed its downstream mammalian target of rapamycin signaling pathway. Largazole also inhibited the proliferation and induced apoptosis of NSCLC and chronic myeloid leukemia (CML) cells (including bone marrow mononuclear cells harvested from CML patients). These results indicate that MSI2 is an emerging therapeutic target for NSCLC and CML, and the MSI2 inhibitor largazole may hold promise as a treatment for these malignancies.

Keywords: Musashi-2; inhibitor; non-small cell lung cancer; chronic myeloid leukemia; largazole.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Depsipeptides / chemistry
  • Depsipeptides / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • Mice
  • Middle Aged
  • Models, Molecular
  • Molecular Docking Simulation
  • Protein Conformation
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Up-Regulation / drug effects

Substances

  • Depsipeptides
  • MSI2 protein, human
  • RNA-Binding Proteins
  • Thiazoles
  • largazole