title: PR55α Subunit of Protein Phosphatase 2A Supports the Tumorigenic and Metastatic Potential of Pancreatic Cancer Cells by Sustaining Hyperactive Oncogenic Signaling.
abstract: The protein phosphatase 2 (PP2A) holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. Based on loss-of-function analysis using PP2A catalytic inhibitors or inhibition via tumor viral antigens, limited studies suggest that PP2A is a putative tumor suppressor. However, PP2A has also been shown to facilitate the activation of oncogenic signaling pathways when associated with specific regulatory subunits. In this study, we investigated the possible oncogenic role of PP2A in pancreatic cancer. We found a striking increase in the expression of PR55α (PPP2R2A), a PP2A regulatory subunit, in pancreatic cancer cells compared with normal pancreatic epithelial cells. Consistently, PR55α expression was markedly elevated in pancreatic ductal adenocarcinoma tissues compared with adjacent normal pancreatic tissues (P < 0.0001) and correlated with poor survival of pancreatic cancer patients (P < 0.0003). RNAi-mediated depletion of PR55α in pancreatic cancer cell lines resulted in diminished phosphorylation of both AKT and ERK1/2 (MAPK3/1) and decreased protein levels of β-catenin (CTNNB1). Accordingly, pancreatic cancer cells with reduced PR55α expression exhibited significantly impaired properties of transformation, including attenuated cell growth, clonogenicity, mobility, and anchorage-independent growth. Moreover, orthotopic implantation of PR55α-depleted pancreatic cancer cells into nude mice resulted in markedly reduced tumorigenicity (P < 0.001) and distant metastases. Together, these results suggest that PR55α promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK, and Wnt. These studies also provide a basis for exploring PR55α as a diagnostic or therapeutic target in pancreatic cancer. Cancer Res; 76(8); 2243-53. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Hein
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Seshacharyulu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Yuri M
authors.initials: YM
authors.lastname: Sheinin
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Michel M
authors.initials: MM
authors.lastname: Ouellette
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Moorthy P
authors.initials: MP
authors.lastname: Ponnusamy
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Mumby
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C512974:PPP2R2A protein, human; D054648:Protein Phosphatase 2