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Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Authors :
Paillas, Salome
Bibeau, Frédéric
Denouël, Amélie
Mollevi, Caroline
Causse, Annick
Denis, Vincent
Vezzio-Vié, Nadia
Marzi, Laetitia
Cortijo, Cédric
Ait-Arsa, Imade
Askari, Nadav
Pourquier, Philippe
Martineau, Pierre
Del Rio, Maguy
Gongora, Celine
Boissière, Florence
Vezzio-Vie, N.
Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1)
Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Département de Pathologie [CHU Caen]
Université de Caen Normandie (UNICAEN)
Normandie Université (NU)-Normandie Université (NU)-CHU Caen
Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)
EndoFrance [CHRU Montpellier]
Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM)
CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Cyclotron Réunion Océan Indien (CYROI)
Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion)
Sanford-Burnham Medical Research Institute
Signalisation et Mecanismes Moleculaires de l'Apoptose
Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Laboratoire d'anatomo-pathologie
CRLCC Val d'Aurelle - Paul Lamarque
Unité de biostatistiques
Validation et identification de nouvelles cibles en oncologie (VINCO)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux]
UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2
Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse )
Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)
IDvet
Laboratoire d'Informatique, de Modélisation et d'optimisation des Systèmes (LIMOS)
Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Mines de St Etienne
CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)
Institut Bergonié [Bordeaux]
UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Source :
Cancer Research, Cancer Research, American Association for Cancer Research, 2011, 71 (3), pp.1041-1049. ⟨10.1158/0008-5472.CAN-10-2726⟩, Cancer Research, American Association for Cancer Research, 2011, 71 (3), pp.1041-9. ⟨10.1158/0008-5472.CAN-10-2726⟩
Publication Year :
2011
Publisher :
HAL CCSD, 2011.

Abstract

Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer. Cancer Res; 71(3); 1041–9. ©2010 AACR.

Subjects

Subjects :
Cancer Research
Pyridines
Colorectal cancer
[SDV]Life Sciences [q-bio]
Cell
Leucovorin
Drug resistance
p38 Mitogen-Activated Protein Kinases
MESH: Drug Synergism
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
MAPK p38
MESH: Protein Kinase Inhibitors
MESH: Animals
Phosphorylation
ComputingMilieux_MISCELLANEOUS
0303 health sciences
Imidazoles
Drug Synergism
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Immunohistochemistry
MESH: Drug Resistance, Neoplasm
3. Good health
Isoenzymes
MESH: Antineoplastic Combined Chemotherapy Protocols
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Colonic Neoplasms
MESH: Isoenzymes
MESH: Camptothecin
Adenocarcinoma
Female
Fluorouracil
MESH: Imidazoles
medicine.drug
MESH: Xenograft Model Antitumor Assays
MAP Kinase Signaling System
MESH: HCT116 Cells
Mice, Nude
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
Irinotecan
Article
03 medical and health sciences
Downregulation and upregulation
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
medicine
MESH: Mice, Nude
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Protein Kinase Inhibitors
MESH: Mice
030304 developmental biology
MESH: Colonic Neoplasms
MESH: Humans
MESH: Phosphorylation
MESH: MAP Kinase Signaling System
MESH: Adenocarcinoma
MESH: Pyridines
Cancer
MESH: Immunohistochemistry
HCT116 Cells
medicine.disease
Xenograft Model Antitumor Assays
MESH: p38 Mitogen-Activated Protein Kinases
SN38
Drug Resistance, Neoplasm
Immunology
Cancer research
Camptothecin
MESH: Leucovorin
MESH: Female
MESH: Fluorouracil

Details

Language :
English
ISSN :
00085472 and 15387445
Database :
OpenAIRE
Journal :
Cancer Research, Cancer Research, American Association for Cancer Research, 2011, 71 (3), pp.1041-1049. ⟨10.1158/0008-5472.CAN-10-2726⟩, Cancer Research, American Association for Cancer Research, 2011, 71 (3), pp.1041-9. ⟨10.1158/0008-5472.CAN-10-2726⟩
Accession number :
edsair.doi.dedup.....eb0bac47b862e56582fb93371ab3dfea
Full Text :
https://doi.org/10.1158/0008-5472.CAN-10-2726⟩