Oncotarget

Research Papers:

Cyclin D1 unbalances the redox status controlling cell adhesion, migration, and drug resistance in myeloma cells

Sophie Bustany, Jérôme Bourgeais, Guergana Tchakarska, Simon Body, Olivier Hérault, Fabrice Gouilleux and Brigitte Sola _

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Oncotarget. 2016; 7:45214-45224. https://doi.org/10.18632/oncotarget.9901

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Abstract

Sophie Bustany1,*, Jérôme Bourgeais2,*, Guergana Tchakarska1,4, Simon Body1, Olivier Hérault2,3, Fabrice Gouilleux2, Brigitte Sola1

1Université de Caen Normandie, EA4652 (MILPAT), MICAH Team, Caen, France

2Université François Rabelais, CNRS UMR 7292 (GICC), LNox Team, Tours, France

3Service d'Hématologie Biologique, CHRU Tours, Tours, France

4Present address: Cytogenetics Laboratory, Research Institute, McGill University Health Centre, Montréal, Canada

*Co-first authors

Correspondence to:

Brigitte Sola, email: brigitte.sola@unicaen.fr

Keywords: reactive oxygen species, p44/42 mitogen-activated protein kinase, pomalidomide, carfilzomib, NADPH oxidase

Received: February 01, 2016     Accepted: May 28, 2016     Published: June 07, 2016

ABSTRACT

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.


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