title: Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells.
abstract: 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 beta1 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 beta1 integrins. beta1 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 beta1 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 beta1 integrin-mediated regulation of Bim degradation may increase the efficacy of drugs, including imatinib, used to treat haematopoietic malignancies.
authors.affiliation: Department of Interdisciplinary Oncology and Experimental Therapeutics Program, H Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, FL, USA. hazlehla@moffitt.usf.edu
authors.forename: L A
authors.initials: LA
authors.lastname: Hazlehurst
authors.forename: R F
authors.initials: RF
authors.lastname: Argilagos
authors.forename: W S
authors.initials: WS
authors.lastname: Dalton
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D002448:Cell Adhesion; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D019012:Integrin beta1 / Q000378:metabolism*; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018365:Neoplasm, Residual; D010879:Piperazines / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D005353:Fibronectins; D005419:Flavonoids; D019012:Integrin beta1; D008565:Membrane Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one