title: PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways.
abstract: Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumors and is generally strongly resistant to currently available chemo- and/or radiotherapy regimens, including targeted molecular therapies. Therefore, unraveling the molecular mechanisms underlying the aggressive behavior of pancreatic cancer is a necessary prerequisite for the development of novel therapeutic approaches. We previously identified the protein placenta-specific 8 (PLAC8, onzin) in a genome-wide search for target genes associated with pancreatic tumor progression and demonstrated that PLAC8 is strongly ectopically expressed in advanced preneoplastic lesions and invasive human PDAC. However, the molecular function of PLAC8 remained unclear, and accumulating evidence suggested its role is highly dependent on cellular and physiologic context. Here, we demonstrate that in contrast to other cellular systems, PLAC8 protein localizes to the inner face of the plasma membrane in pancreatic cancer cells, where it interacts with specific membranous structures in a temporally and spatially stable manner. Inhibition of PLAC8 expression strongly inhibited pancreatic cancer cell growth by attenuating cell-cycle progression, which was associated with transcriptional and/or posttranslational modification of the central cell-cycle regulators CDKN1A, retinoblastoma protein, and cyclin D1 (CCND1), but did not impact autophagy. Moreover, Plac8 deficiency significantly inhibited tumor formation in genetically engineered mouse models of pancreatic cancer. Together, our findings establish PLAC8 as a central mediator of tumor progression in PDAC and as a promising candidate gene for diagnostic and therapeutic targeting.
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Brajesh P
authors.initials: BP
authors.lastname: Kaistha
authors.affiliation: Central Imaging Facility, Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lorenz
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, University Clinic Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Department of Biochemistry and Protein Profiling, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlak
authors.affiliation: Department of Biochemistry and Protein Profiling, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Gierke
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Kreider
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lankat-Buttgereit
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fiedler
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Krattenmacher
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Geisel
authors.affiliation: Medical Systems Biology, University of Ulm, Ulm, Germany.
authors.forename: Johann M
authors.initials: JM
authors.lastname: Kraus
authors.affiliation: Princess Margaret Hospital, University of Toronto, Toronto, Canada.
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Frese
authors.affiliation: CeGaT GmbH, Tübingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kelkenberg
authors.affiliation: Department of Surgery, University Clinic Heidelberg, Heidelberg, Germany.
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.affiliation: Medical Systems Biology, University of Ulm, Ulm, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.affiliation: Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany. malte.buchholz@staff.uni-marburg.de.
authors.forename: Malte
authors.initials: M
authors.lastname: Buchholz
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: C506004:PLAC8 protein, human; C475342:Plac8 protein, mouse; D011506:Proteins