Abstract
BackgroundCell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development.MethodsDevelopment of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis.ResultsOur preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells.ConclusionsOur findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.
Highlights
Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM)
In the model of CAM-DR in mantle cell lymphoma, we found that when malignant cells adhered to the bone marrow stromal cell line, HS-5, the p27Kip1 ubiquitination degradation significantly reduced the accumulation of p27Kip1 and the cell cycle arrest was triggered by an increase in p27Kip1 protein levels [29]
Numbl interacts with integrin β1 To determine whether Numbl interacted with Integrin β1 in vivo, we performed a co-immunoprecipitation experiment
Summary
Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). Berry M,G [10], and other investigators have reported high expression of integrin β1 in highly invasive cancer cells isolated from breast cancer patients with low survival rates. Recent studies have highlighted that integrin β1 mediated adhesion between cancer cells and the ECM can reduce the tumor cell cytotoxicity that is induced by radiotherapy and chemotherapy [13, 14]. Naci D [15] and others have found that integrin β1 mediated adhesion between leukemic cells and the ECM can significantly inhibit the apoptosis induced by chemotherapy drugs. Further lending support to these findings, there is evidence to suggest that adhesion between mantle cell lymphoma (MCL) cells and the ECM is caused, in part, by abnormally elevated expression levels of integrin β1, an important factor of tumor cell resistance to therapy [16]
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