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Voies de mort cellulaire et signalisation au cours de la différenciation mégacaryocytaire de cellules érythroleucémiques humaines (HELs)

Abstract : Current strategies to eradicate cancer cells consist in inducing apoptosis or differentiation of these cells. Several natural substances are used to reactivate the differentiation that is stopped during the cancerous transformation of cells. In 2006, Leger et al, showed the involvement of apoptosis during megakaryocytic differentiation of HELs (human erythroleukemia cell line) by 10 µM of diosgenin. Previous studies talked about the autophagy crucial role during the megakaryocytic differentiation. Thus, the objective of our work is to show the involvement of this cell death pathway called "autophagy" in the differentiated HEL cells by diosgenin. Our results show the stimulation of autophagic flux after treatment of HELs with 10 µM diosgenin. This stimulation is manifested by the overexpression of Atg7 and the accumulation of the LC3-II form as the differentiation progresses. To interrogate the role of autophagy, this pathway was modulated before (2h before) and after (days 2 and 4) the differentiation induction by diosgenin. It was shown that inhibition of autophagy by 3-methyl adenine (3-MA ; 2 mM) represses polyploidy on days 4 and 8 of differentiation while activation of autophagy by metformin (Met ; 0.25 mM) induces no effect regardless of treatment time. Furthermore, modulation of autophagy was shown to affect membrane maturation (glycoprotein V genomic expression) of diosgenin-differentiated HELs. Inhibition of autophagy before and after induction of differentiation by diosgenin, strongly represses GpV expression at days 4 and 8. Whereas activation of autophagy by metformin, activates GpV expression at the end of the differentiation regardless of the treatment time. In parallel, it was shown that modulation of autophagy during HEL megakaryocytic differentiation induced by diosgenin (10 µM) does not affect the DNA fragmentation. In summary, the autophagic pathway is involved during diosgenin (10 µM) induced megakaryocytic differentiation of HELs. To further elucidate the role of autophagy in this process and its interaction with the apoptotic pathway, more investigations should be conducted.
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Dima Diab. Voies de mort cellulaire et signalisation au cours de la différenciation mégacaryocytaire de cellules érythroleucémiques humaines (HELs). Biologie cellulaire. Université de Limoges, 2021. Français. ⟨NNT : 2021LIMO0057⟩. ⟨tel-03553268⟩

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