Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells.
The interactions of multiple myeloma (MM) cells with their microenvironment are crucial for pathogenesis. MM cells could interact differentially with their microenvironment depending on the type of cyclin D they express. We established several clones that constitutively express cyclin D1 from the parental RPMI8226 MM cell line and analyzed the impact of cyclin D1 expression on cell behavior. We performed a gene expression profiling study on cyclin D1-expressing vs. control cells and validated the results by semi-quantitative RT-PCR. The expression of cyclin D1 altered the transcription of genes that control adhesion and migration. We confirmed that cyclin D1 increases cell adhesion to stromal cells and fibronectin, stabilizes F-actin fibers, and enhances chemotaxis and inflammatory chemokine secretion. Both control and cyclin D1-expressing cells were more resistant to acute carfilzomib treatment when cultured on stromal cells than in suspension. However, this resistance was specifically reduced in cyclin D1-expressing cells after pomalidomide pre-treatment that modifies tumor cell/microenvironment interactions. Transcriptomic analysis revealed that cyclin D1 expression was also associated with changes in the expression of genes controlling metabolism. We also found that cyclin D1 expression disrupted the redox balance by producing reactive oxygen species. The resulting oxidative stress activated the p44/42 mitogen-activated protein kinase (or ERK1/2) signaling pathway, increased cell adhesion to fibronectin or stromal cells, and controlled drug sensitivity.Our results have uncovered a new function for cyclin D1 in the control of redox metabolism and interactions of cyclin D1-expressing MM cells with their bone marrow microenvironment.
Université de Caen Normandie, EA4652 (MILPAT), MICAH Team, Caen, France.
Sophie
S
Bustany
Université François Rabelais, CNRS UMR 7292 (GICC), LNOx Team, Tours, France.
Jérôme
J
Bourgeais
Université de Caen Normandie, EA4652 (MILPAT), MICAH Team, Caen, France.|Present address: Cytogenetics Laboratory, Research Institute, McGill University Health Centre, Montréal, Canada.
Guergana
G
Tchakarska
Université de Caen Normandie, EA4652 (MILPAT), MICAH Team, Caen, France.
Simon
S
Body
Université François Rabelais, CNRS UMR 7292 (GICC), LNOx Team, Tours, France.|Service d'Hématologie Biologique, CHRU Tours, Tours, France.
Olivier
O
Hérault
Université François Rabelais, CNRS UMR 7292 (GICC), LNOx Team, Tours, France.
Fabrice
F
Gouilleux
Université de Caen Normandie, EA4652 (MILPAT), MICAH Team, Caen, France.
Brigitte
B
Sola
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D059016:Tumor Microenvironment
C530104:CCND1 protein, human; D018925:Chemokines; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D013792:Thalidomide; C467566:pomalidomide; D048049:Extracellular Signal-Regulated MAP Kinases
NADPH oxidase; carfilzomib; p44/42 mitogen-activated protein kinase; pomalidomide; reactive oxygen species