Azacitidine-resistant SKM1 myeloid cells are defective for AZA-induced mitochondrial apoptosis and autophagy

作者：Cluzeau Thomas; Robert Guillaume; Puissant Alexandre; Jean Michel Karsenti; Cassuto Jill Patrice; Raynaud Sophie; Auberger Patrick^*

来源：Cell Cycle, 2011, 10(14): 2339-2343.

DOI：10.4161/cc.10.15.16308

• azacitidine
• resistance
• apoptosis
• autophagy
• MDS
• AML
• caspases

Azacitidine (AZA) is the current treatment for patients with high-risk myelodysplastic syndrome but resistance is a common feature of AZA-treated patients. To investigate the mechanisms associated with AZA resistance in vitro, we generated AZA-resistant SKM1 myeloid cells called hereafter AZA-R. AZA-R cells exhibit impaired mitochondrial membrane permeabilization and caspase activation in response to AZA compared to their AZA sensitive (AZA-S) counterpart. AZA induced LC3-II accumulation and cathepsin B activity in AZA-S cells two hallmarks of autophagy. AZA-R cells displayed increased basal autophagy but are resistant to AZA-mediated autophagy. Inhibition of autophagy using LC3 siRNA revealed that autophagy is protective in AZA-S cells and AZA-R cells in basal conditions. By contrast, AZA-R cells exhibited impaired autophagy in response to AZA. Collectively, our findings indicate that AZA promotes apoptosis and autophagy in SKM1 cells and that AZA-R cells are resistant to both apoptosis and autophagy induced by AZA.

• 出版日期2011-7-15