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

Oncotarget. 2015 May 10;6(13):10853-67. doi: 10.18632/oncotarget.3414.

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.

Keywords: ErbB2; FOLFIRINOX; chemoresistance; gemcitabine; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / metabolism
  • Camptothecin / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Databases, Genetic
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / metabolism
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm* / genetics
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Irinotecan
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice, SCID
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • RNA Interference
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction / drug effects
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • ABCC2 protein, human
  • Antimetabolites, Antineoplastic
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • RNA, Messenger
  • cif nucleoside transporter
  • Deoxycytidine
  • Irinotecan
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Camptothecin
  • Gemcitabine