title: Characterization of cyclin E expression in multiple myeloma and its functional role in seliciclib-induced apoptotic cell death.
abstract: Multiple Myeloma (MM) is a lymphatic neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to chemotherapy. Drug resistance, differentiation block and increased survival of the MM tumor cells result from high genomic instability. Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of cyclin D, a regulatory protein that governs the activation of key cell cycle regulator--cyclin dependent kinase (CDK). Genomic instability was reported to be affected by over expression of another CDK regulator--cyclin E (CCNE). This occurs early in tumorigenesis in various lymphatic malignancies including CLL, NHL and HL. We therefore sought to investigate the role of cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with siRNA increased the cell sensitivity to seliciclib. Adhesion to FN of hMMCLs was prevented by seliciclib, eliminating adhesion-mediated drug resistance of MM cells. Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that seliciclib may be considered as essential component of modern anti MM drug combination therapy.
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, The Guy Weinshtock Multiple Myeloma Foundation, Tel-Hashomer, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Josefsberg Ben-Yehoshua
authors.forename: Katia
authors.initials: K
authors.lastname: Beider
authors.forename: Avichai
authors.initials: A
authors.lastname: Shimoni
authors.forename: Olga
authors.initials: O
authors.lastname: Ostrovsky
authors.forename: Michal
authors.initials: M
authors.lastname: Samookh
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D000077546:Roscovitine
chemical_list: C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D005419:Flavonoids; D015513:Oncogene Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D000077546:Roscovitine; D019938:Cyclin D1; C077990:alvocidib