Novel microtubule inhibitor MPT0B098 inhibits hypoxia-induced epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma

  • J Biomed Sci. 2018 Mar 28;25(1):28. doi: 10.1186/s12929-018-0432-6.
I-Ting Tsai  1  2 ,  Ching-Chuan Kuo  3  4  5 ,  Jing-Ping Liou  6 ,  Jang-Yang Chang  7  8  9  10
Affiliations
  • 1. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
  • 2. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 3. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
  • 4. Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 5. Graduate Program for Aging, China Medical University, Taichung, Taiwan.
  • 6. College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 7. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. [email protected].
  • 8. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. [email protected].
  • 9. Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. [email protected].
  • 10. Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. [email protected].
PMID: 29592811 DOI: 10.1186/s12929-018-0432-6
Abstract

Background: Tumor hypoxia-induced epithelial-mesenchymal transition (EMT) is critical in promoting Cancer metastasis. We recently discovered a novel microtubule inhibitor, MPT0B098, that employs a novel antitumor mechanism. It destabilizes hypoxia-inducible factor (HIF)-1α mRNA by blocking the function of human antigen R. Thus, we proposed that MPT0B098 modulates hypoxia-induced EMT.

Methods: In vitro IC50 values were determined through the methylene blue dye assay. To investigate molecular events, reverse transcriptase-polymerase chain reaction, Western blotting, immunofluorescence staining, and wound healing assay were employed.

Results: MPT0B098 significantly inhibited HIF-1α expression, epithelial-to-mesenchymal morphology changes, and migratory ability in the human head and neck squamous cell carcinoma cell line OEC-M1. Furthermore, after MPT0B098 treatment, the expression of two mesenchymal markers, vimentin and N-Cadherin, was downregulated under hypoxic conditions. Moreover, MPT0B098 suppressed hypoxia-induced EMT in part by inhibiting EMT-activating transcription factors, Twist and SNAI2/Slug. In addition, the inhibition of hypoxia-induced F-actin rearrangement and focal adhesion kinase phosphorylation may have contributed to suppression of EMT by MPT0B098in OEC-M1 cells. MPT0B098 significantly inhibited transforming growth factor(TGF)-β-induced phosphorylation of receptor-associated SMAD2/3 by downregulating TGF-β mRNA and protein expression.

Conclusions: Taken together, this study provides a novel insight into the role of MPT0B098 in inhibiting hypoxia-induced EMT, suggesting its potential use for treating head and neck cancers.

Keywords
Epithelial to mesenchymal transition; Head and neck cancer; Hypoxia; Microtubule inhibitor; TGF-β.
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