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 ␣41-integrin or ␣51-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.
Medulloblastoma (MB) is a high-grade pediatric brain malignancy that originates from neuronal precursors located in the posterior cranial fossa. In this study, we evaluated the role of STAT3 and IL-6 in a tumor microenvironment mediated drug resistance in human MBs. We established that the Group 3 MB cell line, Med8A, is chemosensitive (hence Med8A-S), and this is correlated with a basal low phosphorylated state of STAT3, while treatment with IL-6 induced robust increases in pY705-STAT3. Via incremental selection with vincristine, we derived the stably chemoresistant variant, Med8A-R, that exhibited multi-drug resistance, enhanced IL-6 induced pY705-STAT3 levels, and increased IL6R expression. Consequently, abrogation of STAT3 or IL6R expression in Med8A-R led to restored chemosensitivity to vincristine, highlighting a prominent role for canonical IL-6/STAT3 signaling in acquired drug resistance. Furthermore, Med8A-S subjected to conditioning exposure with IL-6, termed Med8A-IL6+ cells, exhibited enhanced vincristine resistance, increased expression of pY705-STAT3 and IL6R, and increased secretion of IL-6. When cocultured with Med8A-IL6+ cells, Med8A-S cells exhibited increased pY705-STAT3 and increased IL-6 secretion, suggesting a cytokine feedback loop responsible for amplifying STAT3 activity. Similar IL-6 induced phenomena were also observed in the Group 3 MB cell lines, D283 and D341, including increased pY705-STAT3, drug resistance, IL-6 secretion and IL6R expression. Our study unveiled autocrine IL-6 as a promoter of STAT3 signaling in development of drug resistance, and suggests therapeutic benefits for targeting the IL-6/STAT3 signaling axis in Group 3 MBs.
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