Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan.
Apoptosis. 2013 Nov;18(11):1403-1415. doi: 10.1007/s10495-013-0872-0.
Exposure of acute promyelocytic leukemia (APL) cells to all-trans retinoic acid (ATRA) increases levels of Mcl-1, however, the implication of ATRA-mediated expressions of Mcl-1 in these cells remains to be fully elucidated. This study found that exposure of NB4 and PL-21 cells to ATRA increased levels of Mcl-1 in association with phosphorylation of c-jun N-terminus kinases. Down-regulation of Mcl-1 by a small interfering (siRNA) or an inhibitor of JNK significantly potentiated the ability of ATRA to induce differentiation and apoptosis in these cells. On the other hand, the anti-leukemia effects of ATRA were blunted when Mcl-1 was forced expressed in NB4 and PL-21 cells as well as leukemia cells isolated from individuals with APL. Furthermore, down-regulation of Mcl-1 by an siRNA sensitized non-APL U937 and KG-1 leukemia cells to ATRA-mediated differentiation and apoptosis. Taken together, inhibition of Mcl-1 might be useful to potentiate the action of ATRA in APL as well as non-APL AML cells.
全反式维甲酸（ATRA）暴露可增加急性早幼粒细胞白血病（APL）细胞中 Mcl-1 的水平，但 ATRA 介导的 Mcl-1 表达在这些细胞中的影响仍有待充分阐明。本研究发现，NB4 和 PL-21 细胞暴露于 ATRA 后，Mcl-1 水平升高，并伴有 c-jun N 端激酶的磷酸化。通过小干扰（siRNA）或 JNK 抑制剂下调 Mcl-1，可显著增强 ATRA 诱导这些细胞分化和凋亡的能力。另一方面，当在 NB4 和 PL-21 细胞以及 APL 患者分离的白血病细胞中强制表达 Mcl-1 时，ATRA 的抗白血病作用被减弱。此外，siRNA 下调 Mcl-1 可使非 APL U937 和 KG-1 白血病细胞对 ATRA 介导的分化和凋亡敏感。总之，抑制 Mcl-1 可能有助于增强 ATRA 在 APL 以及非 APL AML 细胞中的作用。
