The membrane-proximal KXGFFKR motif of ?-integrin mediates chemoresistance.

ABSTRACT: Cell adhesion-mediated drug resistance contributes to minimal residual disease and relapse in hematological malignancies. Here, we show that adhesion of Jurkat T-acute lymphoblastic leukemia cells to substrates engaging ?4?1-integrin or ?5?1-integrin promotes chemoresistance to doxorubicin-induced apoptosis. Reconstituted expression of ?4?, a truncated ?4-integrin with KXGFFKR as the cytoplasmic motif, in ?4-deficient cells promoted chemoresistance to doxorubicin in a manner independent of ?4-mediated adhesion. The adhesion-independent chemoresistance did not require ?1-integrin as the heterodimeric pair, since expression of Tac?, a monomeric nonintegrin transmembrane protein fused to the juxtamembrane KXGFFKR, was sufficient to reproduce the phenomenon. The requirement for integrin-mediated adhesion in stimulation of Akt phosphorylation and activation was bypassed for cells expressing ?4? and Tac?. Cells expressing ?4? and Tac? exhibited a high influx of extracellular Ca(2+), and inhibition of Ca(2+) channels with verapamil attenuated the adhesion-independent chemoresistance. Tac? cells also exhibited greater rates of drug efflux. ?4? and Tac? interacted with the Ca(2+)-binding protein calreticulin, in a manner dependent on the KXGFFKR motif. Adhesion-mediated engagement of ?4-integrins promoted an increased calreticulin-?4 association and greater influx of extracellular Ca(2+) than in nonadherent cells. The ?-integrin KXGFFKR motif is involved in adhesion-mediated control of chemoresistance in T cells.

SUBMITTER: Liu CC 

PROVIDER: S-EPMC3811891 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other