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.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) represent the third and the fifth most common malignancy in Asian and Western countries, respectively (Ferlay et al, 2015)
Antibodies against p63, p63 phosphorylated at Ser160/162, liver kinase B1 (LKB1), LKB1 phosphorylated at Ser428, p38MAPK, p38MAPK phosphorylated at Thr180/Tyr182, AMPKα, AMPKα phosphorylated at Thr172, signal transducer and activator of transcription 3 (STAT3), STAT3 phosphorylated at Tyr705, survivin, caspase 3 active form and PARP were from Cell Signaling Technology (Danvers, MA, United States)
3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assay was employed to assess the effects of WMJ-J compounds (WMJ-J-01∼10) (Supplementary Figure S1) on cell viability in FaDu, SCC9, and SCC25 human HNSCC cell lines
Summary
Head and neck squamous cell carcinomas (HNSCCs) represent the third and the fifth most common malignancy in Asian and Western countries, respectively (Ferlay et al, 2015). They account for approximately 550,000 new cases and 380,000 deaths annually (Global Burden of Disease Cancer Collaboration et al, 2017). The smallest member of the inhibitor of apoptosis protein (IAP) family, regulates cellular homeostasis with functions beyond inhibiting apoptosis (Srinivasula and Ashwell, 2008) It underlies various cellular events such as mitosis (Altieri, 2008), cell migration, angiogenesis, and metastasis (Ryan et al, 2009; Mehrotra et al, 2010; Altieri, 2013). Pharmacological targeting of the p63survivin cascade is a potential therapeutic strategy in HNSCC treatment
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