The survival of IL-6-dependent myeloma cells critically relies on their capability to transit the G1 to S phase interval of the cell cycle.
Interleukin-6 (IL-6) has an essential role in the initial progression of myeloma cell tumours. IL-6 triggers proliferation of these cells via the Ras-mitogen-activated protein kinase (MAPK) cascade and is thought to promote their survival via signal transducer and activator of transcription (STAT) pathway-dependent regulation of Bcl-2 family antiapoptotic members. Using IL-6-dependent murine B9 hybridoma/plasmacytoma cells, we here report that exiting the cell cycle G1 phase is a crucial step contributing to maintain viability. We show that (1) drug-mediated reversible G1 arrest triggered apoptosis despite the presence of IL-6; (2) a short IL-6 pulse to G1-arrested cells was sufficient to induce S phase entry and prevent apoptosis; and (3) phorbol ester and related derivatives promoted S phase entry and survival of IL-6-starved cells without up-regulating bcl-XL expression. Furthermore, that the MAPK kinase (MEK) 1/2 inhibitor, U0126, blocked proliferation and induced death of B9 cells indicate that IL-6 may not exert its survival effect primarily through bcl-XL and emphasizes the key role of Ras-MAPK cascade elements in the regulation of myeloma growth/viability.
Côté
Serge
S
Département de Recherche et Développement, Héma-Québec, Sainte-Foy, QC, Canada. scote@hema-quebec.qc.ac
Lemieux
Réal
R
Simard
Carl
C
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006825:Hybridomas; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D016196:S Phase; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D017493:Leukocyte Common Antigens; D013755:Tetradecanoylphorbol Acetate