Anti-tumor mechanisms of WMJ-J2, a novel aliphatic hydroxamate-based compound, in HCT116 colorectal cancer cells

[Speaker] Ming-Jen Hsu:1
[Co-author] Wei-Jan Huang:2, Yu-Han Huang:3, Meng-Chieh Yu:1
1:Department of Pharmacology, Taipei Medical University, Taiwan, 2:Graduate Institute of Pharmacognosy, Taipei Medical University, Taiwan, 3:Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taiwan

Background: Growing evidence shows that hydroxamate-based compounds exhibit broad-spectrum pharmacological properties including anti-tumor activity. It thus attracts much attention in the field of drug discovery. However, the precise mechanisms underlying hydroxamate derivatives' anti-tumor actions remains incomplete understood. Methods: In this study, we investigated the anti-tumor mechanisms of a novel aliphatic hydroxamate derivative, WMJ-J2, in HCT116 colorectal cancer cells. Results: WMJ-J2 caused G2/M cell cycle arrest and apoptosis in HCT116 cells. These actions were associated with liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38MAPK) activation, as well as the modulation of survivin and p21. LKB1-AMPK-p38MAPK signaling blockade reduced WMJ-J2's enhancing effects on survivin reduction. WMJ-J2 also caused p53 phosphorylation and acetylation. WMJ-J2's actions on p21 were reduced in p53-null HCT116 cells. In contrast, WMJ-J2-induced survivin reduction was not altered in p53-null HCT116 cells. WMJ-J2's enhancing effects in survivin reduction were reduced in the presence of MG132, a proteasome inhibitor. Moreover, WMJ-J2 induced alpha-tubulin acetylation and interfered with microtubule assembly. Transfection with HDAC6-Flag or HDAC8-Flag abrogated WMJ-J2's enhancing effect on alpha-tubulin acetylation. Furthermore, WMJ-J2 suppressed the growth of subcutaneous xenografts of HCT116 cells in vivo. Conclusions: WMJ-J2-induced HCT116 cell death may involve LKB1-AMPK-p38MAPK-p53-survivin signaling pathway. Disruption of microtubule assembly may also contribute to WMJ-J2's actions in HCT116 cells. These results suggest that WMJ-J2 may be a potential drug candidate and warrant the clinical development in the treatment of colorectal cancer cells
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