title: Pro-differentiating effects of a synthetic flavagline on human teratocarcinomal cancer stem-like cells.
abstract: As initiators of the carcinogenic process, cancer stem cells (CSCs) are considered as new targets for anti-cancer therapies. However, these cells are hidden in the cancer bulk and remain relatively insensitive to chemotherapy, which targets their proliferative capacities. Alternatively, growing evidences have pointed out that a differentiation therapy could adversely affect these cells, which consequently should lose their self-renewal properties and become less aggressive. In order to evaluate the differentiation potential of an emerging class of anti-cancer drugs, we used the poorly differentiated teratocarcinomal cell as a model of Oct4-expressing CSC and determined the molecular mechanisms induced by the highly active flavagline FL3. The drug, administrated at sublethal concentration and for long period, was able to downregulate the expression levels of the stemness factors Oct4 and Nanog at both transcriptional and translational levels, concomitantly with a decrease of clonogenicity. The appearance of specific neural markers further demonstrated the differentiation properties of FL3. Interestingly, an expression of active caspase-3 and an upregulation of the expression of the germ cell nuclear factor were observed in treated cells; this suggests that the suppression of Oct4 expression required for the induction of differentiation involves overlapping mechanisms of protein degradation and gene repression. Finally, this study shows that FL3, like all-trans retinoic acid (ATRA), acts as a differentiation inducer of teratocarcinomal cells. Thus, FL3 offers an alternative possibility for cancer treatment since it could target the carcinogenic process by inducing the differentiation of ATRA-resistant and Oct4-expressing CSCs, without toxic side effects on normal cells.
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Fathi
authors.initials: F
authors.lastname: Emhemmed
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ali Azouaou
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: UMR 7369 CNRS, Laboratoire Matrice Extracellulaire et Dynamique Cellulaire, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Appert-Collin
authors.affiliation: UMR 7369 CNRS, Laboratoire Matrice Extracellulaire et Dynamique Cellulaire, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, Reims, France.
authors.forename: Amar
authors.initials: A
authors.lastname: Bennasroune
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, B.P. 60024, 67401, Illkirch, France.
authors.forename: Valérie B
authors.initials: VB
authors.lastname: Schini-Kerth
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Muller
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.|Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, China.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, B.P. 60024, 67401, Illkirch, France. guy.fuhrmann@unistra.fr.
authors.forename: Guy
authors.initials: G
authors.lastname: Fuhrmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D000071317:Nanog Homeobox Protein / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D050814:Octamer Transcription Factor-3; D014212:Tretinoin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D014212:Tretinoin; D053148:Caspase 3
keywords: Cancer stem cells; Differentiation; Flavagline; Oct4; Teratocarcinoma