Beta1 integrin mediated adhesion increases Bim protein degradation and contributes to drug resistance in leukaemia cells

Br J Haematol. 2007 Jan;136(2):269-75. doi: 10.1111/j.1365-2141.2006.06435.x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bcl-2-Like Protein 11
  • Benzamides
  • Cell Adhesion
  • Drug Resistance, Neoplasm*
  • Fibronectins / metabolism
  • Flavonoids / pharmacology
  • Humans
  • Imatinib Mesylate
  • Integrin beta1 / metabolism*
  • K562 Cells
  • Leukemia / drug therapy
  • Leukemia / metabolism*
  • Leukemia / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm, Residual
  • Piperazines / therapeutic use
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Pyrimidines / therapeutic use
  • RNA Interference
  • RNA, Small Interfering / pharmacology


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Benzamides
  • Fibronectins
  • Flavonoids
  • Integrin beta1
  • Membrane Proteins
  • Piperazines
  • Proto-Oncogene Proteins
  • Pyrimidines
  • RNA, Small Interfering
  • Imatinib Mesylate
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one