title: Cyclin D1 sensitizes myeloma cells to endoplasmic reticulum stress-mediated apoptosis by activating the unfolded protein response pathway.
abstract: BACKGROUND
  Cyclin D1 and its kinase partners control cell cycle progression. Cyclin D1 is frequently deregulated in various cancers, including malignant hemopathies, and tumor cells display uncontrolled cell proliferation. Cyclin D1 is not expressed in the B-cell lineage but is found in multiple myeloma (MM) cells in almost 50% of patients with this condition. Paradoxically, cyclin D1 expression is associated with a good prognosis and longer overall survival in MM patients.
  
  
  METHODS
  We used two independent MM cell lines (RPMI 8226 and LP1) to generate several clones stably expressing either the green fluorescent protein (GFP) or a GFP-cyclin D1 fusion protein, and we analyzed the properties acquired following cyclin D1 expression.
  
  
  RESULTS
  Whole-genome expression analysis in the cell clones indicated that cyclin D1 profoundly modified several cellular functions, including the regulation of apoptotic cell death. We studied the apoptotic response of GFP- and GFP-cyclin D1-expressing clones to bortezomib-treatment. We found that the apoptotic response occurred faster and was of a greater amplitude in cyclin D1-expressing cells. Cyclin D1 expression enhanced the caspase-dependent apoptosis mediated by the intrinsic mitochondrial pathway. More importantly, cyclin D1 also activated the unfolded protein response (UPR) and induced endoplasmic reticulum (ER) stress-mediated apoptosis.
  
  
  CONCLUSIONS
  The ER is well known to be a crucial regulator of plasma cell death and it plays the same role in their malignant counterparts, myeloma cells. This role involves activation of the UPR controlled at least in part by cyclin D1.
authors.affiliation: Normandie Univ, UNICAEN, EA4652, Caen, France. sophie.bustany@gmail.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bustany
authors.affiliation: Normandie Univ, UNICAEN, EA4652, Caen, France. julie.cahu@gmail.com.
authors.forename: Julie
authors.initials: J
authors.lastname: Cahu
authors.affiliation: Plateforme SNP, Transcriptome & Epigénomique, CHU, Angers, France. PhGuardiola@chu-angers.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Guardiola
authors.affiliation: Normandie Univ, UNICAEN, EA4652, Caen, France. brigitte.sola@unicaen.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: C530104:CCND1 protein, human; D009363:Neoplasm Proteins; D019938:Cyclin D1