Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Cancer Biol Ther. 2010 Dec 1;10(11):1157-67. doi: 10.4161/cbt.10.11.13556.
All-trans retinoic acid (ATRA) has been successfully used in differentiation therapy for acute promyelocytic leukemia (APL) in the clinic. ATRA-induced differentiation of leukemia cells is accompanied by a G0/G1 arrest, yet how ATRA couples cell cycle arrest to differentiation remains largely unknown. Here we observed that the ubiquitin-proteasome pathway (UPP) was activated upon ATRA treatment in the human acute myeloid leukemia cell lines, NB4 and HL-60, as represented by the accumulation of ubiquitinated proteins, the up-regulation of ubiquitin mRNA and increased 20S proteasome activity. Interestingly, we found that complete inhibition of proteasome activity suppressed ATRA-induced proliferation/differentiation (P/D) transition in both cell lines. Furthermore, we demonstrate that the exact protein contributing to this phenomenon is different in these two cell lines. Cyclin-dependent kinase 2 (CDK2) and Cyclin E were degraded by the UPP; they accumulated significantly after complete inhibition of the proteasome in ATRA-treated NB4 and HL-60 cells, respectively. These findings suggested that the UPP might be indispensable in the ATRA-induced G0/G1 arrest and differentiation of leukemia cells. The exact protein degraded by the UPP to promote the myeloid maturation program set in motion by the retinoid may be cell type dependent.
全反式维甲酸（ATRA）已成功用于临床治疗急性早幼粒细胞白血病（APL）的分化治疗。ATRA 诱导白血病细胞分化伴随着 G0/G1 期阻滞，但 ATRA 如何将细胞周期阻滞与分化偶联仍然知之甚少。在这里，我们观察到，人急性髓系白血病细胞系 NB4 和 HL-60 在 ATRA 处理后，泛素-蛋白酶体途径（UPP）被激活，表现为泛素化蛋白的积累、泛素 mRNA 的上调和 20S 蛋白酶体活性的增加。有趣的是，我们发现完全抑制蛋白酶体活性抑制了这两种细胞系中 ATRA 诱导的增殖/分化（P/D）转换。此外，我们证明，在这两种细胞系中，导致这种现象的确切蛋白是不同的。细胞周期蛋白依赖性激酶 2（CDK2）和细胞周期蛋白 E 被 UPP 降解；在 ATRA 处理的 NB4 和 HL-60 细胞中，蛋白酶体完全抑制后，它们分别显著积累。这些发现表明，UPP 可能在 ATRA 诱导的白血病细胞 G0/G1 期阻滞和分化中不可或缺。UPP 降解的确切蛋白可能与细胞类型有关，以促进视黄酸引发的髓系成熟程序。
