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

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.

• Authors: I-Ting Tsai, Ching-Chuan Kuo, Jing-Ping Liou, Jang-Yang Chang
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 25 Issue 1 Pg. 28 (Mar 28 2018) ISSN: 1423-0127 [Electronic] England
• PMID: 29592811 (Publication Type: Journal Article)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Indoles
• MPT0B098
• Sulfonamides
• Tubulin Modulators

Topics

• Carcinoma, Squamous Cell (physiopathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (drug effects)
• Head and Neck Neoplasms (physiopathology)
• Humans
• Hypoxia (physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors)
• Indoles (pharmacology)
• Squamous Cell Carcinoma of Head and Neck
• Sulfonamides (pharmacology)
• Tubulin Modulators (pharmacology)