CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells
Journal
Oral Oncology
Journal Volume
48
Journal Issue
7
Pages
585-593
Date Issued
2012
Author(s)
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a worldwide disease with aggressive course and dismal outcome. Bortezomib, a proteasome inhibitor, has been approved clinically for hematological malignancies and demonstrated to have activities against solid tumors in vitro through inhibition of NF-kB activity. Here, we disclose that bortezomib induced apoptosis of HNSCC cells in vitro and in vivo through inhibition of cancerous inhibitor of protein phosphatase 2A (CIP2A)-mediated PP2A dependent Akt activation. HNSCC cells, including Ca9-22, SAS, and SCC-25, were treated with bortezomib and evaluated for viability, apoptosis, and signal transduction. Three HNSCC cells, including Ca9-22, SAS, and SCC-25, were sensitive to bortezomib with marked growth inhibition and apoptosis. We found phospho-Akt (p-Akt, Ser473) played a significant role in bortezomib-induced apoptosis. The activity of PP2A was significantly increased after the treatment of bortezomib without alternation of PP2A level or the dynamic interaction of PP2A-Akt. Silencing PP2A by small interference RNA (siRNA) abolished bortezomib-induced Akt inhibition and apoptosis. In addition, bortezomib inhibited CIP2A in pre-translational level in a dose- and time-dependent manner. Over-expression of CIP2A up-regulated p-Akt and protected HNSCC cells from bortezomib-induced apoptosis. Furthermore, xenograft model showed that bortezomib down-regulated CIP2A and p-Akt in SAS tumor cells. CIP2A is demonstrated to be a new therapeutic target of bortezomib in HNSCC. ? 2012 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
bortezomib; cancerous inhibitor of protein phosphatase 2A; phosphoprotein phosphatase 2A; protein kinase B; serine; small interfering RNA; unclassified drug; animal experiment; animal model; apoptosis; article; cancer cell; cancer inhibition; cell viability; drug mechanism; enzyme activation; enzyme activity; enzyme inhibition; enzyme phosphorylation; head and neck cancer; head and neck squamous cell carcinoma; in vitro study; in vivo study; male; mouse; nonhuman; priority journal; protein expression; signal transduction; squamous cell carcinoma; Animals; Antineoplastic Agents; Apoptosis; Autoantigens; Blotting, Western; Boronic Acids; Carcinoma, Squamous Cell; Cell Line, Tumor; Head and Neck Neoplasms; Male; Membrane Proteins; Mice; Mice, Nude; Neoplasms, Experimental; Polymerase Chain Reaction; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Pyrazines; RNA, Small Interfering; Signal Transduction
Type
journal article