title: Small molecule inhibitor YM155-mediated activation of death receptor 5 is crucial for chemotherapy-induced apoptosis in pancreatic carcinoma.
abstract: Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor that has shown antitumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the antitumor effect of YM155 with in vitro studies in cultured cells, and in vivo studies using a mouse xenograft model. Our data demonstrated that YM155 reduced the expression of survivin; however, downregulation of survivin itself is insufficient to induce apoptosis in pancreatic cancer cells. We showed for the first time that treatment with YM155 increased death receptor 5 (DR5) expression in pancreatic cancer cells. We found that YM155 induced apoptosis by broad-spectrum inhibition of IAP family member proteins (e.g., CIAP1/2 and FLIP) and induced proapoptotic Bak protein upregulation and activation; the antitumor effect of YM155 treatment with either the DR5 agonist lexatumumab or gemcitabine on pancreatic cancer cells was synergistic. Our data also revealed that YM155 inhibits tumor growth in vivo, without apparent toxicity to the noncancerous human pancreatic ductal epithelial cell line. Together, these findings suggest that YM155 could be a novel therapeutic agent for pancreatic cancer.
authors.affiliation: Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida. Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China. liu@pathology.ufl.edu zhaoxiangxuan@gmail.com.
authors.forename: Xiangxuan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: William M
authors.initials: WM
authors.lastname: Puszyk
authors.affiliation: Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China.
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: George
authors.affiliation: Department of Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota. Department of Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Robertson
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida. liu@pathology.ufl.edu zhaoxiangxuan@gmail.com.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000077022:Survivin; D003841:Deoxycytidine; C510234:lexatumumab; C523798:sepantronium; D000093542:Gemcitabine