Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
Blood. 2010 Sep 30;116(13):2324-31. doi: 10.1182/blood-2010-01-261040. Epub 2010 Jun 23.
Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid and/or arsenic trioxide represents a paradigm in targeted cancer therapy because these drugs cause clinical remission by affecting the stability of the fusion oncoprotein promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARA). The authors of previous studies have implicated the ubiquitin-proteasome pathway as the main mechanism involved in therapy-induced PML/RARA degradation. Here we have investigated a role of autophagy, a protein degradation pathway that involves proteolysis of intracellular material within lysosomes. We found that both all-trans retinoic acid and arsenic trioxide induce autophagy via the mammalian target of rapamycin pathway in APL cells and that autophagic degradation contributes significantly both to the basal turnover as well as the therapy-induced proteolysis of PML/RARA. In addition, we observed a correlation between autophagy and therapy-induced differentiation of APL cells. Given the central role of the PML/RARA oncoprotein in APL pathogenesis, this study highlights an important role of autophagy in the development and treatment of this disease.
用全反式维甲酸和/或三氧化二砷治疗急性早幼粒细胞白血病 (APL) 代表了靶向癌症治疗的范例，因为这些药物通过影响融合致癌蛋白早幼粒细胞白血病 (PML)/维甲酸受体 alpha (RARA) 的稳定性而导致临床缓解。先前研究的作者已经将泛素-蛋白酶体途径作为涉及治疗诱导的 PML/RARA 降解的主要机制。在这里，我们研究了自噬的作用，自噬是一种涉及溶酶体内细胞内物质蛋白水解的蛋白质降解途径。我们发现，全反式维甲酸和三氧化二砷都通过哺乳动物雷帕霉素靶蛋白途径诱导 APL 细胞中的自噬，并且自噬降解对 PML/RARA 的基础周转率和治疗诱导的蛋白水解都有重要贡献。此外，我们观察到自噬与 APL 细胞的治疗诱导分化之间存在相关性。鉴于 PML/RARA 癌蛋白在 APL 发病机制中的核心作用，本研究强调了自噬在这种疾病的发展和治疗中的重要作用。
