title: Xanthohumol-Mediated Suppression of Notch1 Signaling Is Associated with Antitumor Activity in Human Pancreatic Cancer Cells.
abstract: Pancreatic cancer remains a lethal disease with limited treatment options. At the time of diagnosis, approximately 80% of these patients present with unresectable tumors caused by either locally advanced lesions or progressive metastatic growth. Therefore, development of novel treatment strategies and new therapeutics is needed. Xanthohumol (XN) has emerged as a potential compound that inhibits various types of cancer, but the molecular mechanism underlying the effects of XN remains unclear. In the present study, we have assessed the efficacy of XN on pancreatic cancer cell lines (AsPC-1, PANC-1, L3.6pl, MiaPaCa-2, 512, and 651) against cell growth in real time and using colony-forming assays. Treatment with XN resulted in reduction in cellular proliferation in a dose- and time-dependent manner. The growth suppression effect of XN in pancreatic cancer cell lines is due to increased apoptosis via the inhibition of the Notch1 signaling pathway, as evidenced by reduction in Notch1, HES-1, and survivin both at mRNA as well as protein levels. Notch1 promoter reporter analysis after XN treatment indicated that XN downregulates Notch promoter activity. Importantly, overexpression of active Notch1 in XN-treated pancreatic cancer cells resulted in negation of growth suppression. Taken together, these findings demonstrate, for the first time, that the growth suppressive effect of XN in pancreatic cancer cells is mainly mediated by Notch1 reduction.
authors.affiliation: Division of Surgical Oncology and Medical College of Wisconsin Cancer Center, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Selvi
authors.initials: S
authors.lastname: Kunnimalaiyaan
authors.affiliation: Department of Surgery, Section of Pancreatobiliary Surgery, University of Florida-Gainesville, Gainesville, Florida.
authors.forename: Jose
authors.initials: J
authors.lastname: Trevino
authors.affiliation: Division of Surgical Oncology and Medical College of Wisconsin Cancer Center, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Susan
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Division of Surgical Oncology and Medical College of Wisconsin Cancer Center, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: T Clark
authors.initials: TC
authors.lastname: Gamblin
authors.affiliation: Division of Surgical Oncology and Medical College of Wisconsin Cancer Center, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin. mkunnima@mcw.edu.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011427:Propiophenones / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D013997:Time Factors; D000072056:Transcription Factor HES-1; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D005419:Flavonoids; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D011427:Propiophenones; D051881:Receptor, Notch1; D000077022:Survivin; D000072056:Transcription Factor HES-1; C107489:BIRC5 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human; C104536:xanthohumol