A novel hydroxamate-based compound WMJ-J-09 causes head and neck squamous cell carcinoma cell death via LKB1-AMPK-p38MAPK-p63-survivin cascade

Chia Sheng Yen, Cheuk Sing Choy, Wei Jan Huang, Shiu Wen Huang, Pin Ye Lai, Meng Chieh Yu, Ching Shiue, Ya Fen Hsu, Ming Jen Hsu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. However, the precise mechanisms underlying hydroxamate derivative-induced cancer cell death remain incomplete understood. In this study, we explored the anti-tumor mechanisms of a novel aliphatic hydroxamate-based compound, WMJ-J-09, in FaDu head and neck squamous cell carcinoma (HNSCC) cells. WMJ-J-09 induced G2/M cell cycle arrest and apoptosis in FaDu cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, transcription factor p63 phosphorylation, as well as modulation of p21 and survivin. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J-09's enhancing effects in p63 phosphorylation, p21 elevation and survivin reduction. Moreover, WMJ-J-09 caused an increase in α-tubulin acetylation and interfered with microtubule assembly. Furthermore, WMJ-J-09 suppressed the growth of subcutaneous FaDu xenografts in vivo. Taken together, WMJ-J-09-induced FaDu cell death may involve LKB1-AMPK-p38MAPK-p63-survivin signaling cascade. HDACs inhibition and disruption of microtubule assembly may also contribute to WMJ-J-09's actions in FaDu cells. This study suggests that WMJ-J-09 may be a potential lead compound and warrant the clinical development in the treatment of HNSCC.

Original languageEnglish
Article number167
Pages (from-to)1-17
Number of pages17
JournalFrontiers in Pharmacology
Volume9
Issue numberMAR
DOIs
Publication statusPublished - Mar 1 2018

Keywords

  • Aliphatic hydroxamate
  • Head and neck squamous cell carcinoma (HNSCC)
  • Liver kinase B1 (LKB1)
  • P63
  • Survivin
  • survivin
  • liver kinase b1
  • p63
  • head and neck squamous
  • aliphatic hydroxamate, liver kinase B1 (LKB1), p63
  • lkb1
  • cell carcinoma
  • aliphatic hydroxamate

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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