Upregulated expression and function of the alpha 4 beta 1 integrin in multiple myeloma cells resistant to bortezomib

Resumen:
The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival, and resistance to different anti-MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The alpha 4 beta 1 integrin is a main adhesion receptor mediating MM cell-stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion-mediated drug resistance (CAM-DR) and MM cell apoptosis. Whether decreased alpha 4 beta 1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of alpha 4 beta 1 function could boost MM cell survival and disease progression. Using BTZ-resistant MM cells, we found that they not only rescue their alpha 4 beta 1 expression, but its levels were higher than in parental cells. Increased alpha 4 beta 1 expression in resistant cells correlated with enhanced alpha 4 beta 1-mediated cell lodging in the BM, and with disease progression. BTZ-resistant MM cells displayed enhanced NF-kappa B pathway activation relative to parental counterparts, which contributed to upregulated alpha 4 expression and to alpha 4 beta 1-dependent MM cell adhesion. These data emphasize the upregulation of alpha 4 beta 1 expression and function as a key event during resistance to BTZ in MM, which might indirectly contribute to stabilize this resistance, as stronger MM cell ...