title: A potential therapeutic application of SET/I2PP2A inhibitor OP449 for canine T-cell lymphoma.
abstract: Lymphoma is one of the most common malignant tumors in canine. Chemotherapy results in a high rate of remission; however, relapse and clinical drug resistance are usually seen within a year. Protein phosphatase 2A (PP2A) acts as a tumor suppressor and plays a critical role in mammalian cell transformation. Increased protein levels of SET, endogenous PP2A inhibitor, have been reported to correlate with poor prognosis in human leukemia. Here, we test the potential therapeutic role for a SET antagonist in canine lymphoma. We observed SET protein levels increased in multiple canine lymphoma cell lines compared with primary peripheral blood cells. A novel SET antagonist OP449 increased PP2A activity and effectively killed SET high-expressing canine lymphoma cells, but not SET low-expressing cells. Caspase-3 activation and enhanced Annexin V positive staining were observed after OP449 treatment, suggesting apoptotic cell death by OP449. Consistent with this, pan-caspase inhibitor Z-VAD-FMK blocked OP449 induced cell death. These data demonstrated the potential therapeutic application of SET antagonists for canine lymphoma.
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fujiwara
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Yabe
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.forename: Takuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D056488:Histone Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056488:Histone Chaperones; C583613:OP449 peptide; D010455:Peptides; D014157:Transcription Factors