Yen Chia-Sheng, Choy Cheuk-Sing, Huang Wei-Jan, Huang Shiu-Wen, Lai Pin-Ye, Yu Meng-Chieh, Shiue Ching, Hsu Ya-Fen, Hsu Ming-Jen
Department of General Surgery, Chi Mei Medical Center, Tainan, Taiwan.
Department of Emergency, Min-Sheng General Hospital, Taoyuan, Taiwan.
Front Pharmacol. 2018 Mar 1;9:167. doi: 10.3389/fphar.2018.00167. eCollection 2018.
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 . 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.
越来越多的证据表明，异羟肟酸类化合物具有包括抗肿瘤活性在内的广谱药理特性。然而，异羟肟酸衍生物诱导癌细胞死亡的确切机制仍未完全清楚。在本研究中，我们探讨了一种新型脂肪族异羟肟酸类化合物WMJ-J-09对FaDu头颈部鳞状细胞癌（HNSCC）细胞的抗肿瘤机制。WMJ-J-09诱导FaDu细胞发生G2/M期细胞周期阻滞和凋亡。这些作用与肝激酶B1（LKB1）、AMP活化蛋白激酶（AMPK）和p38丝裂原活化蛋白激酶（p38MAPK）的激活、转录因子p63的磷酸化以及p21和生存素的调节有关。LKB1-AMPK-p38MAPK信号通路阻断降低了WMJ-J-09对p63磷酸化、p21升高和生存素降低的增强作用。此外，WMJ-J-09导致α-微管蛋白乙酰化增加并干扰微管组装。此外，WMJ-J-09抑制了皮下FaDu异种移植瘤的生长。综上所述，WMJ-J-09诱导的FaDu细胞死亡可能涉及LKB1-AMPK-p38MAPK-p63-生存素信号级联反应。组蛋白去乙酰化酶（HDACs）抑制和微管组装破坏也可能有助于WMJ-J-09在FaDu细胞中的作用。本研究表明，WMJ-J-09可能是一种潜在的先导化合物，值得在HNSCC治疗中进行临床开发。
