title: Garcinol downregulates Notch1 signaling via modulating miR-200c and suppresses oncogenic properties of PANC-1 cancer stem-like cells.
abstract: Pancreatic cancer represents one of the most aggressive types of malignancy due to its high resistance toward most clinically available treatments. The presence of pancreatic cancer stem-like cells (CSCs) has been attributed to the intrinsically high resistance and highly metastatic potential of this disease. Here, we identified and isolated pancreatic CSCs using the side population (SP) method from human pancreatic cancer cell line, PANC-1. We then compared the SP and non-SP PANC-1 cells genetically. PANC-1 SP cells exhibited CSC properties including enhanced self-renewal ability, increased metastatic potential, and resistance toward gemcitabine treatment. These cancer stem-like phenotypes were supported by their enhanced expression of ABCG2, Oct4, and CD44. A traditional plant-derived antioxidant, garcinol, has been implicated for its anticancer properties. Here, we found that garcinol treatment to PANC-1 SP cells significantly suppressed the stem-like properties of PANC-1 SP cells and metastatic potential by downregulating the expression of Mcl-1, EZH2, ABCG2, Gli-1, and Notch1. More importantly, garcinol treatment led to the upregulation of several tumor suppressor microRNAs, and miR-200c increased by garcinol treatment was found to target and downregulate Notch1. Thus, PANC-1 SP cells may serve as a model for studying drug-resistant pancreatic CSCs, and garcinol has the potential as an antagonist against pancreatic CSCs.
authors.affiliation: Department of Surgery, Cathay General Hospital SiJhih, New Taipei City, Taiwan.|School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.|School of Medicine, Taipei Medical University, Taipei City, Taiwan.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Chien-Min
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan.|The Ph.D. Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taiwan.
authors.forename: Yan-Jiun
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: The Ph.D. Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taiwan.|Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Li
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Lei-Li
authors.initials: LL
authors.lastname: Ting
authors.affiliation: Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Cheyu
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Jeng-Fong
authors.initials: JF
authors.lastname: Chiou
authors.affiliation: The Ph.D. Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taiwan.
authors.forename: Alexander T H
authors.initials: ATH
authors.lastname: Wu
authors.affiliation: Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000008:administration & dosage*
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D013729:Terpenes; C054597:garcinol
keywords: Notch1; drug resistance; garcinol; pancreatic cancer stem-like cells; side population cells