Adhesion to fibronectin induces p27^sup Kip1^ nuclear accumulation through down-regulation of Jab1 and contributes to cell adhesion-mediated drug resistance (CAM-DR) in RPMI 8,226 cells

Mounting evidence has been shown that integrin-mediated cellular adhesion confers resistance to chemotherapy of multiple myeloma. The molecular mechanism underlying cell adhesion-mediated drug resistance (CAM-DR) is, however, poorly understood. In this report, we demonstrated that RPMI 8,226 cells accumulated p27^sup Kip1^ in the nucleus when they were adhered to fibronectin (FN). The adhesion-mediated p27^sup Kip1^ nuclear recruitment was regulated via the down-regulation of Jab1, a negative regulator of cell cycle. Overexpression of Jab1 reversed the elevated p27^sup Kip1^ in the nucleus, which needed phosphorylation of p27^sup Kip1^ on Serine 10, whereas inhibition of Jab1 by siRNA further increased the elevated p27^sup Kip1^. Furthermore, we found overexpression of Jab1 did not affect 8,226 cells adhesion to FN, but reversed doxorubicin or mitoxantrone-induced CAM-DR phenotype. In conclusion, our data suggest that Jab1 plays an important role in CAM-DR, which depends on pSer10-p27^sup Kip1^-mediated subcellular localization of p27^sup Kip1^. The understanding of this novel molecular mechanism may prove valuable in designing new therapeutic approaches for CAM-DR in Multiple myeloma.[PUBLICATION ABSTRACT]