title: The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2.
abstract: Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers because of a lack of early diagnostic markers and efficient therapeutics. The fluorinated analog of deoxycytidine, gemcitabine and emerging FOLFIRINOX protocol (5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin) are the main chemotherapies to treat PDAC. The ErbB2/HER2 oncogenic receptor is commonly overexpressed in PDAC. In this context, we aimed to decipher the ErbB2-mediated mechanisms of chemoresistance to the two main chemotherapy protocols used to treat PDAC.ErbB2 knocking down (KD) in CAPAN-1 and CAPAN-2 cells led to an increased sensitivity to gemcitabine and an increased resistance to irinotecan/SN-38 both in vitro and in vivo (subcutaneous xenografts) This was correlated to an increase of hCNT1 and hCNT3 transporters and ABCG2, MRP1 and MRP2 ATP-binding cassette transporters expression and resistance to cell death. We also show that MRP2 is repressed following activation of JNK, Erk1/2 and NF-κB pathways by ErbB2. Finally, in datasets of human PDAC samples, ErbB2 and MRP2 expression was conversely correlated. Altogether, we propose that ErbB2 mediates several intracellular mechanisms linked to PDAC cell chemoresistance that may represent potential targets in order to ameliorate chemotherapy response and allow stratification of patients eligible for either gemcitabine or FOLFIRINOX treatment.
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.|Université Lille Nord de France, Lille cedex 59000, France.|Centre Hospitalier Régional et Universitaire de Lille, Lille cedex 59037, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skrypek
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.|Université Lille Nord de France, Lille cedex 59000, France.|Centre Hospitalier Régional et Universitaire de Lille, Lille cedex 59037, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Vasseur
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.|Université Lille Nord de France, Lille cedex 59000, France.|Centre Hospitalier Régional et Universitaire de Lille, Lille cedex 59037, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.|Université Lille Nord de France, Lille cedex 59000, France.|Centre Hospitalier Régional et Universitaire de Lille, Lille cedex 59037, France.
authors.forename: Bélinda
authors.initials: B
authors.lastname: Duchêne
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.|Université Lille Nord de France, Lille cedex 59000, France.|Centre Hospitalier Régional et Universitaire de Lille, Lille cedex 59037, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 "Mucins, epithelial differentiation and carcinogenesis", Lille cedex 59045, France.|Université Lille Nord de France, Lille cedex 59000, France.|Centre Hospitalier Régional et Universitaire de Lille, Lille cedex 59037, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jonckheere
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D030541:Databases, Genetic; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D000077146:Irinotecan; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016513:Mice, SCID; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D002166:Camptothecin; D003841:Deoxycytidine; D000077146:Irinotecan; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000093542:Gemcitabine; C000715087:ABCC2 protein, human; C065171:cif nucleoside transporter; C508053:ERBB2 protein, human
keywords: ErbB2; FOLFIRINOX; chemoresistance; gemcitabine; pancreatic cancer