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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
- Source :
- Oncotarget, Oncotarget, 2015, 6 (13), pp.10853-1067. ⟨10.18632/oncotarget.3414⟩, ResearcherID, Oncotarget, Impact journals, 2015, 6 (13), pp.10853-1067. ⟨10.18632/oncotarget.3414⟩
- Publication Year :
- 2015
- Publisher :
- HAL CCSD, 2015.
-
Abstract
- International audience; 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.
- Subjects :
- Male
Antimetabolites, Antineoplastic
endocrine system diseases
Receptor, ErbB-2
pancreatic cancer
[SDV.CAN]Life Sciences [q-bio]/Cancer
Mice, SCID
Irinotecan
Transfection
Deoxycytidine
ErbB2
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
Databases, Genetic
Animals
Humans
RNA, Messenger
neoplasms
Cell Death
gemcitabine
Membrane Transport Proteins
chemoresistance
Xenograft Model Antitumor Assays
Multidrug Resistance-Associated Protein 2
digestive system diseases
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
FOLFIRINOX
Drug Resistance, Neoplasm
Gene Knockdown Techniques
Camptothecin
RNA Interference
Multidrug Resistance-Associated Proteins
Signal Transduction
Research Paper
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Database :
- OpenAIRE
- Journal :
- Oncotarget, Oncotarget, 2015, 6 (13), pp.10853-1067. ⟨10.18632/oncotarget.3414⟩, ResearcherID, Oncotarget, Impact journals, 2015, 6 (13), pp.10853-1067. ⟨10.18632/oncotarget.3414⟩
- Accession number :
- edsair.pmid.dedup....8a67c22a59d06253587fa2c0f13f0d83