Activation of snail and EMT-like signaling via the IKKαβ/NF-κB pathway in Apicidin-resistant HA22T hepatocellular carcinoma cells.
The molecular and phenotypic associations between chemo- or radio-resistance and the acquisition of epithelial-mesenchymal transition (EMT)-like phenotype are tightly related in cancer cells. Wnt/β- catenin and NF-κB signaling pathways play crucial roles in EMT induction. Apicidin-resistant (Apicidin- R) HA22T cells are known to activate the Wnt/β-catenin signaling pathway and MMP-2 expression via the IGF-IR/PI3K/Akt signaling pathway to enhance metastatic effects of cancer cells. In this study, we further investigated if Apicidin-R HA22T cells actually underwent EMT. In Apicidin-R HA22T cells, E-cadherin protein level was reduced but Vimentin, Snail and Twist were significantly activated. Activation of p-IKKαβ and p-IκBα was also observed in Apicidin-R HA22T cells. Apicidin-R HA22T cells displayed even higher NF-κB nuclear accumulation. Snail was enhanced but GSK3-β was reduced. However, unphosphorylated GSK3-β protein level was totally reversed when the Snail-specific siRNA was applied in a knockdown experiment. Taken together, Apicidin-R HA22T cells could potentiate aggressive metastasis behavior due to up-regulation of Snail expression and promoted EMT effects via the IKKαβ/NF-κB pathway. In addition, Snail might decrease the GSK3-β level resulting in extraordinarily activation of Wnt/β-catenin signaling pathway.
Institute of Medical and Molecular Toxicology and Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, Republic of China.
Chuan-Chou
CC
Tu
Li-Hao
LH
Cheng
Hsi-Hsien
HH
Hsu
Li-Mien
LM
Chen
Yueh-Min
YM
Lin
Ming-Cheng
MC
Chen
Nien-Hung
NH
Lee
Fuu-Jen
FJ
Tsai
Chih-Yang
CY
Huang
Wen-Jun
WJ
Wu
D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*
D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D010456:Peptides, Cyclic; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C102351:apicidin; D000071679:Glycogen Synthase Kinase 3 beta; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3