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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.

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https://hal.univ-angers.fr/hal-03329049
Contributeur : Okina Université d'Angers <>
Soumis le : lundi 30 août 2021 - 15:40:41
Dernière modification le : mardi 31 août 2021 - 03:23:57

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Nina Fenouille, Sebastien Grosso, Su Yunchao, Didier Mary, Rodolphe Pontier-Bres, et al.. Calpain 2-dependent IκBα degradation mediates CPT-11 secondary resistance in colorectal cancer xenografts. Journal of Pathology, 2012, 227 (1), pp.118-29. ⟨10.1002/path.3034⟩. ⟨hal-03329049⟩

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