title: SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 - a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Wuebben
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Wilder
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
authors.forename: Jesse L
authors.initials: JL
authors.lastname: Cox
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Grunkemeyer
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Caffrey
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.|Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA.
authors.forename: Angie
authors.initials: A
authors.lastname: Rizzino
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C117307:KRAS protein, human; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D034741:RNA, Small Interfering; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C560077:trametinib; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: AKT inhibitors; MEK inhibitors; SOX2; drug resistance; pancreatic cancer