title: HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress.
abstract: Multiple myeloma (MM) is still an incurable hematological malignancy. Despite recent progress due to new anti-myeloma agents, the pathology is characterized by a high frequency of de novo or acquired resistance. Delineating the mechanisms of MM resistance is essential for therapeutic advances. We previously showed that long-term genotoxic stress induces the establishment of a senescence-associated secretory phenotype, a pro-inflammatory response that favors the emergence of cells with cancer stem-like properties. Here, we studied the short-term response of MM cells following treatment with various DNA damaging agents such as the energetic C-ion irradiation. MM cells are highly resistant to all treatments and do not enter apoptosis after they arrest cycling at the G2 phase. Although the DNA damage response pathway was activated, DNA breaks remained chronically in damaged MM cells. We found, using a transcriptomic approach that RAD50, a major DNA repair gene was downregulated early after genotoxic stress. In two gerosuppression situations: induction of hypoxia and inhibition of the mammalian target of rapamycin (mTOR) pathway, we observed, after the treatment with a DNA damaging agent, a normalization of RAD50 expression concomitant with the absence of cell cycle arrest. We propose that combining inhibitors of mTOR with genotoxic agents could avoid MM cells to senesce and secrete pro-inflammatory factors responsible for cancer stem-like cell emergence and, in turn, relapse of MM patients.
authors.affiliation: a Normandie Univ, UNICAEN, EA4652, MICAH team , Caen , France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Coudre
authors.affiliation: a Normandie Univ, UNICAEN, EA4652, MICAH team , Caen , France.
authors.forename: Julien
authors.initials: J
authors.lastname: Alani
authors.affiliation: b Centenary Institute, University of Sydney , Sydney , Australia.
authors.forename: William
authors.initials: W
authors.lastname: Ritchie
authors.affiliation: c Institut Curie, INSERM U1021, CNRS UMR3347 , Orsay , France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.affiliation: a Normandie Univ, UNICAEN, EA4652, MICAH team , Caen , France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
authors.affiliation: a Normandie Univ, UNICAEN, EA4652, MICAH team , Caen , France.
authors.forename: Julie
authors.initials: J
authors.lastname: Cahu
mesh_terms: D017766:Acid Anhydride Hydrolases; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D011839:Radiation, Ionizing; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D014965:X-Rays
chemical_list: D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058570:TOR Serine-Threonine Kinases; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D020123:Sirolimus
keywords: DNA damage response; DNA repair; cancer stem-like cell; cell cycle arrest; irradiation; mTOR; senescence