Adhesion to fibronectin induces p27Kip1 nuclear accumulation through down-regulation of Jab1 and contributes to cell adhesion-mediated drug resistance (CAM-DR) in RPMI 8,226 cells

Abstract

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(Kip1) in the nucleus when they were adhered to fibronectin (FN). The adhesion-mediated p27(Kip1) nuclear recruitment was regulated via the down-regulation of Jab1, a negative regulator of cell cycle. Overexpression of Jab1 reversed the elevated p27(Kip1) in the nucleus, which needed phosphorylation of p27(Kip1) on Serine 10, whereas inhibition of Jab1 by siRNA further increased the elevated p27(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(Kip1)-mediated subcellular localization of p27(Kip1). The understanding of this novel molecular mechanism may prove valuable in designing new therapeutic approaches for CAM-DR in Multiple myeloma.

Expression of vaccinia-related kinase 1 (VRK1) accelerates cell proliferation but overcomes cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma

“…Previously, our laboratory has discovered that adhesion of multiple myeloma cells to FN can confer a form of drug resistance, and the adhesion status of MM cells may be of outstanding significance for their response to therapeutic drugs (30,31,37) . In this research the relationship between VRK1 expression and adhesive ability of MM cells was investigated.…”

Overexpression of TRIP6 promotes tumor proliferation and reverses cell adhesion-mediated drug resistance (CAM-DR) via regulating nuclear p27Kip1 expression in non-Hodgkin’s lymphoma

“…In this report, we showed that adhesion to FN decreased TRIP6 expression, thereby increasing nuclear p27 Kip1 expression via decreasing phosphorylation of p27 Kip1 at T157. As nuclear p27 Kip1 expression is closely associated with CAM-DR phenotype [6], we then proceeded to investigate whether manipulation of TRIP6-mediated pT157-p27 Kip1 levels had any effect on the CAM-DR phenotype. Intriguingly, cell cycle progression induced by TRIP6 was also arrested or accelerated when transfected with myc-T157A or myc-T157D, respectively.…”

“…Previous study demonstrated that knockdown of TRIP6 in glioblastoma or ovarian cancer can elevate nuclear p27 Kip1 expression [10]. As we know, adhesion of tumor cells to FN can induce cell cycle arrest and protect tumor cells from chemotherapeutic drug-induced apoptosis via increasing nuclear p27 Kip1 protein expression [5,6]. Consequently, we asked whether TRIP6 overcame CAM-DR phenotype by regulating nuclear p27 Kip1 expression.…”

“…Previous studies have shown that adhesion of tumor cells to fibronectin (FN), one of the bone marrow microenvironment components, could induce cell cycle arrest and protect tumor cells from apoptosis via increasing p27 Kip1 protein expression [5]. A recent study also demonstrated that adhesion of multiple myeloma RPMI 8226 cells to FN can induce p27 Kip1 nuclear accumulation through downregulation of Jab1 and contribute to CAM-DR, suggesting that p27 Kip1 plays a key role in CAM-DR [6]. However, how adhesion of Xiaobing Miao and Xiaohong Xu contributed equally to this work.…”

Cell adhesion downregulates the expression of Homer1b/c and contributes to drug resistance in multiple myeloma cells

“…is thought to be a major obstacle in the treatment of myeloma (13,(22)(23)(24)(25). To investigate the role of Homer1b/c in CAM-DR, we built the MM cell adhesion model, in which RPMI-8226 and U266 cells were adherent to the FN and HS-5 cells (3).…”