title: ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells.
abstract: Acute promyelocytic leukemia (APL) results from a blockade of granulocyte differentiation at the promyelocytic stage. All-trans retinoic acid (ATRA) induces clinical remission in APL patients by enhancing the rapid differentiation of APL cells and the clearance of PML-RARα, APL's hallmark oncoprotein. In the present study, we demonstrated that both autophagy and Beclin 1, an autophagic protein, are upregulated during the course of ATRA-induced neutrophil/granulocyte differentiation of an APL-derived cell line named NB4 cells. This induction of autophagy is associated with downregulation of Bcl-2 and inhibition of mTOR activity. Small interfering RNA-mediated knockdown of BECN1 expression enhances apoptosis triggered by ATRA in NB4 cells but does not affect the differentiation process. These results provide evidence that the upregulation of Beclin 1 by ATRA constitutes an anti-apoptotic signal for maintaining the viability of mature APL cells, but has no crucial effect on the granulocytic differentiation. This finding may help to elucidate the mechanisms involved in ATRA resistance of APL patients, and in the ATRA syndrome caused by an accumulation of mature APL cells.
authors.affiliation: INSERM U916 VINCO, Institut Bergonié, Bordeaux, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Trocoli
authors.forename: Julie
authors.initials: J
authors.lastname: Mathieu
authors.forename: Muriel
authors.initials: M
authors.lastname: Priault
authors.forename: Josy
authors.initials: J
authors.lastname: Reiffers
authors.forename: Sylvie
authors.initials: S
authors.lastname: Souquère
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.forename: Françoise
authors.initials: F
authors.lastname: Besançon
authors.forename: Mojgan
authors.initials: M
authors.lastname: Djavaheri-Mergny
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D001343:Autophagy; D000071186:Beclin-1; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D008854:Microscopy, Electron / Q000379:methods; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014212:Tretinoin