Different Types of Cell Cycle- and Apoptosis- Related Gene Expressions Alter in Corticosteroid-, Vincristine-, and Melphalan-Resistant U-266 Multiple Myeloma Cell Lines

摘要

Objective: Deregulation of the cell cycle and apoptosis mechanisms in normal cells causes many problems, including cancer.In this study, a genome-wide expression analysis of cell cycle- and apoptosis-related genes in corticosteroid-, vincristine-, andmelphalan-resistant U-266 multiple myeloma cell lines was conducted.Materials and Methods: Resistant U-266 sublines were induced by application of each drug by stepwise dose increments.Resistance gained by the cells was confirmed with XTT cytotoxicity assay and microarray analyses were carried out. Amongthe cell cycle- and apoptosis-related gene expressions, alterations of more than 2-fold were considered significant.Results: Cyclin E2 was drastically overexpressed in the vincristine-resistant subline and a general upregulation was observedfor various cyclin-dependent kinases. Some of the cyclin-dependent kinase inhibitor encoding genes were downregulatedin resistant sublines in general. Tumor necrosis factor receptor genes were generally downregulated in corticosteroid- andmelphalan-resistant U-266 sublines. Different types of effector caspases were downregulated in all resistant sublines. Ceramidemetabolism genes seemed to be changed in favor of survival, especially in the melphalan-resistant subline.Conclusion: This report shows that different types of chemotherapeutic drugs alter different apoptotic and cell cycle-relatedgene expressions and, as a result, may cause drug-resistant phenotypes in U-266 multiple myeloma cell lines. Among thosegene expressions, the most drastic increase in cyclin E2 could be important for the survival of vincristine-resistant U-266 celllines, whereas alteration of ceramide metabolism genes could be important in melphalan resistance.