WMJ-8-B, a novel hydroxamate derivative, induces MDA-MB-231 breast cancer cell death via the SHP-1-STAT3-survivin cascade

  • Br J Pharmacol. 2017 Sep;174(17):2941-2961. doi: 10.1111/bph.13929.
Yu-Fan Chuang  1 ,  Shiu-Wen Huang  2 ,  Ya-Fen Hsu  3 ,  Meng-Chieh Yu  3  4 ,  George Ou  5 ,  Wei-Jan Huang  6 ,  Ming-Jen Hsu  1  4
Affiliations
  • 1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 3. Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
  • 4. Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5. Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 6. Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
PMID: 28646512 DOI: 10.1111/bph.13929
Abstract

Background and purpose: Histone deacetylase (HDAC) inhibitors have been demonstrate to have broad-spectrum anti-tumour properties and have attracted lots of attention in the field of drug discovery. However, the underlying anti-tumour mechanisms of HDAC inhibitors remain incompletely understood. In this study, we aimed to characterize the underlying mechanisms through which the novel hydroxamate-based HDAC Inhibitor, WMJ-8-B, induces the death of MDA-MB-231 breast Cancer cells.

Experimental approach: Effects of WMJ-8-B on cell viability, cell cycle distribution, Apoptosis and signalling molecules were analysed by the MTT assay, flowcytometric analysis, immunoblotting, reporter assay, chromatin immunoprecipitation analysis and use of siRNAs. A xenograft model was used to determine anti-tumour effects of WMJ-8-B in vivo.

Key results: WMJ-8-B induced Survivin reduction, G2/M cell cycle arrest and Apoptosis in MDA-MB-231 cells. STAT3 phosphorylation, transactivity and its binding to the Survivin promoter region were reduced in WMJ-8-B-treated cells. WMJ-8-B activated the protein Phosphatase SHP-1 and when SHP-1 signalling was blocked, the effects of WMJ-8-B on STAT3 phosphorylation and Survivin levels were abolished. However, WMJ-8-B increased the transcription factor Sp1 binding to the p21 promoter region and enhanced p21 levels. Moreover, WMJ-8-B induced α-tubulin acetylation and disrupted microtubule assembly. Inhibition of HDACs was shown to contribute to WMJ-8-B's actions. Furthermore, WMJ-8-B suppressed the growth of MDA-MB-231 xenografts in mammary fat pads in vivo.

Conclusions and implications: The SHP-1-STAT3-survivin and Sp1-p21 cascades are involved in WMJ-8-B-induced MDA-MB-231 breast Cancer cell death. These results also indicate the potential of WMJ-8-B as a lead compound for treatment of breast Cancer and warrant its clinical development.

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