title: Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer.
abstract: Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease.
  
  
  CONCLUSIONS
  The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer.
authors.affiliation: Authors' Affiliations: Departments of Molecular and Medical Genetics.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Farrell
authors.affiliation: Authors' Affiliations: Departments of Molecular and Medical Genetics.
authors.forename: Brittany
authors.initials: B
authors.lastname: Allen-Petersen
authors.affiliation: Authors' Affiliations: Departments of Molecular and Medical Genetics.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Daniel
authors.affiliation: Authors' Affiliations: Departments of Molecular and Medical Genetics.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Departments of Molecular and Medical Genetics.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon;
authors.forename: Sarah
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon;
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.affiliation: Oncotide Pharmaceuticals Inc., Research Triangle Park;
authors.forename: Jessica
authors.initials: J
authors.lastname: Oddo
authors.affiliation: Oncotide Pharmaceuticals Inc., Research Triangle Park; Department of Neurology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.affiliation: Hematology and Oncology, and.
authors.forename: Charles
authors.initials: C
authors.lastname: Lopez
authors.affiliation: Oncotide Pharmaceuticals Inc., Research Triangle Park; Division of Hematology, Department of Medicine, and.
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.affiliation: Surgery.
authors.forename: Brett
authors.initials: B
authors.lastname: Sheppard
authors.affiliation: Authors' Affiliations: Departments of Molecular and Medical Genetics, searsr@ohsu.edu.
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D056488:Histone Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C583613:OP449 peptide; D010455:Peptides; C513473:SET protein, human; D014157:Transcription Factors; D054648:Protein Phosphatase 2