β1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells

It has been shown that the tumour microenvironment confers resistance to chemotherapy. Specifically, it was previously reported that adhesion of haematopoietic tumour cells to fibronectin (FN) via beta 1 integrins confers a multi-drug resistance phenotype commonly referred to as cell adhesion mediated drug resistance. The present study showed that the pro-apoptotic BCL-2 family member Bim was reduced when leukaemia cells were adherent to FN via beta 1 integrins. beta 1 integrin-mediated regulation of Bim in K562 cells was demonstrated to be partly a result of increased proteasomal-mediated degradation of Bim protein levels, and proteasome inhibitors prevent Bim degradation. Increased degradation of Bim was not related to activation of the mitogen-activated protein kinase pathway, as adhesion of K562 cells caused a reduction in phospho-extracellular signal-related kinase (ERK)1/2 levels. In addition, pharmacological inhibition of MAP/ERK (MEK) with PD98059 did not increase Bim levels. Reducing Bim levels by short hairpin RNA targeting inhibited imatinib and mitoxantrone-induced cell death. These results showed that beta 1 integrin-mediated adhesion regulates Bim degradation and may contribute to the minimal residual disease associated with many haematopoietic malignancies. Together our data indicate that disrupting beta 1 integrin-mediated regulation of Bim degradation may increase the efficacy of drugs, including imatinib, used to treat haematopoietic malignancies.