title: Calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance in colorectal cancer xenografts.
abstract: CPT-11 (irinotecan), the first-line chemotherapy for advanced stage colorectal cancer, remains inactive in about half of patients (primary chemoresistance) and almost all initial responders develop secondary resistance after several courses of treatment (8 months on average). Nude mice bearing HT-29 colon cancer xenografts were treated with CPT-11 and/or an NF-κB inhibitor for two courses. We confirm that NF-κB inhibition potentiated CPT-11 anti-tumoural effect after the first course of treatment. However, tumours grew again at the end of the second course of treatment, generating resistant tumours. We observed an increase in the basal NF-κB activation in resistant tumours and in two resistant sublines, either obtained from resistant HT-29 tumours (HT-29R cells) or generated in vitro (RSN cells). The decrease of NF-κB activation in HT-29R and RSN cells by stable transfections with the super-repressor form of IκBα augmented their sensitivity to CPT-11. Comparing gene expression profiles of HT-29 and HT-29R cells, we identified the S100A10/Annexin A2 complex and calpain 2 as over-expressed potential NF-κB inducers. SiRNA silencing of calpain 2 but not of S100A10 and/or annexin A2, resulted in a decrease in NF-κB activation, an increase in cellular levels of IκBα and a partial restoration of the CPT-11 sensitivity in both HT-29R and RSN cells, suggesting that calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance. Thus, targeted therapies directed against calpain 2 may represent a novel strategy to enhance the anti-cancer efficacy of CPT-11.
authors: INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France.
authors: Nina
authors: N
authors: Fenouille
authors: Sebastien
authors: S
authors: Grosso
authors: Su
authors: S
authors: Yunchao
authors: Didier
authors: D
authors: Mary
authors: Rodolphe
authors: R
authors: Pontier-Bres
authors: Véronique
authors: V
authors: Imbert
authors: Dorota
authors: D
authors: Czerucka
authors: François-Xavier
authors: FX
authors: Caroli-Bosc
authors: Jean-François
authors: JF
authors: Peyron
authors: Patricia
authors: P
authors: Lagadec
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077146:Irinotecan; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016328:NF-kappa B / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D011743:Pyrimidines / Q000494:pharmacology; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D000970:Antineoplastic Agents; D002154:Calpain; D002166:Camptothecin; D020672:I-kappa B Proteins; D000077146:Irinotecan; D016328:NF-kappa B; D011743:Pyrimidines; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10; C519899:AS602868; C570925:Capn2 protein, mouse