title: CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells.
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.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, No. 7 Chung-Shan S Rd., Taipei, Taiwan.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lin
authors.forename: Kuei-Chiu
authors.initials: KC
authors.lastname: Chen
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D016133:Polymerase Chain Reaction; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; D001897:Boronic Acids; C573112:KIAA1524 protein, mouse; D008565:Membrane Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2