title: The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1.
abstract: Combination chemotherapy for the treatment of pancreatic cancer commonly employs gemcitabine with an EGFR inhibitor such as erlotinib. Here, we show that the retinoic acid derivative, ABPN, exhibits more potent anticancer effects than erlotinib, while exhibiting less toxicity toward noncancerous human control cells. Low micromolar concentrations of ABPN induced apoptosis in BxPC3 and HPAC pancreatic cancer cell lines, concomitant with a reduction in phosphorylated EGFR as well as decreased ErbB3, Met and BRUCE protein levels. The degradation of ErbB3 is a result of proteasomal degradation, possibly due to the ABPN-dependent upregulation of Nrdp1. Administration of ABPN showed significant reductions in tumor size when tested using a mouse xenograft model, with higher potency than erlotinib at the same concentration. Analysis of the tumors demonstrated that ABPN treatment suppressed ErbB3 and Met and induced Nrdp1 in vivo. The data suggest that ABPN may be more suitable in combination chemotherapy with gemcitabine than the more widely used EGFR inhibitor, erlotinib.
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA, Department of Agricultural Biotechnology, Seoul National University, Advanced Institutes of Convergence Technology, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA, Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, MN 55454, USA.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Shin
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Traditional Alcoholic Beverage Research Team, Korea Food Research Institute, Seongnam, Republic of Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Yuhan Research Institute, Yuhan Corporation, Giheung-gu, Yongin-si 416-1, Republic of Korea.
authors.forename: Lee
authors.initials: L
authors.lastname: Farrand
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: Department of Bioscience and Biotechnology/Institute of Bioscience, BK21 Graduate Program, Sejong University, Seoul, Republic of Korea, CheBiGen Inc, BioPark infrastructure BI. Business, 452-79 Jang-Dong, Jeonju, Jeollabukdo, Republic of Korea.
authors.forename: Soo-Jong
authors.initials: SJ
authors.lastname: Um
authors.affiliation: CheBiGen Inc, BioPark infrastructure BI. Business, 452-79 Jang-Dong, Jeonju, Jeollabukdo, Republic of Korea.
authors.forename: Hong-Sig
authors.initials: HS
authors.lastname: Sin
authors.affiliation: CheBiGen Inc, BioPark infrastructure BI. Business, 452-79 Jang-Dong, Jeonju, Jeollabukdo, Republic of Korea.
authors.forename: Youn-Ja
authors.initials: YJ
authors.lastname: Kwon
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA, Department of Molecular Pathology, The Afﬁliated Cancer Hospital, Zhengzhou University, Zhengzhou, China and.
authors.forename: Chengjuan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Advanced Institutes of Convergence Technology, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Advanced Institutes of Convergence Technology, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Cellular and Molecular Biology, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA, zgdong@hi.umn.edu.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C480262:4-amino-2-(butyrylamino)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoate; D000970:Antineoplastic Agents; D012176:Retinoids; D003841:Deoxycytidine; D014212:Tretinoin; D000069347:Erlotinib Hydrochloride; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; C581292:ERBB3 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3; D046988:Proteasome Endopeptidase Complex; D005472:Fluorouracil; D000093542:Gemcitabine