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Front. Pharmacol. | doi: 10.3389/fphar.2018.00167

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

  • 1Department of General Surgery, Chi-Mei Medical Center, Taiwan
  • 2Department of Emergency, Min Sheng General Hospital, Taiwan
  • 3Graduate Institute of Pharmacognosy, Taipei Medical University, Taiwan
  • 4Department of Medical Research, Taipei Medical University Hospital, Taiwan
  • 5Graduate Institute of Medical Sciences, Taipei Medical University, Taiwan
  • 6Department of Pharmacology, Taipei Medical University, Taiwan
  • 7Department of Surgery, Landseed Hospital, Taiwan

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 remains 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 the modulation of p21 and survivin. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J-09’s enhancing effects in inducing 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.

Keywords: Aliphatic hydroxamate, Liver Kinase B1 (LKB1), p63, Head and neck squamous cell carcinoma (HNSCC), Survivin.

Received: 12 Jan 2018; Accepted: 15 Feb 2018.

Edited by:

Robert Clarke, Georgetown University, United States

Reviewed by:

Jochen Lorch, Dana–Farber Cancer Institute, United States
Dana Hashim, International Agency For Research On Cancer (IARC), France  

Copyright: © 2018 Yen, Choy, Huang, Huang, Lai, Yu, Shiue, Hsu and Hsu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Ming-Jen Hsu, Taipei Medical University, Department of Pharmacology, Taipei, Taiwan, Aspirin@tmu.edu.tw