Studzinski George P, Wang Xuening, Ji Yan, Wang Qing, Zhang Yingyu, Kutner Andrzej, Harrison Jonathan S
Department of Pathology and Medicine, UMDNJ, New Jersey Medical School, Newark 07103, USA.
J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):47-55. doi: 10.1016/j.jsbmb.2005.06.010. Epub 2005 Jul 25.
The evidence for the promising potential for derivatives of Vitamin D (deltanoids) in the treatment of myeloid leukemias is increasing, but currently is not matched by the understanding of the precise mechanisms by which these anti-neoplastic effects are achieved. Unlike solid tumors in which growth retardation by deltanoids appears to result from inhibition of cell proliferation and the promotion of cell death by apoptosis, control of myeloid leukemia proliferation by deltanoids results from the induction of differentiation of the immature myelo-monocytic cells towards functional monocytic cells. We present here the accumulating evidence that a pathway that is initiated by deltanoid activation of Vitamin D receptor (VDR) and leads to monocytic differentiation of human myeloblastic HL60 cells, includes the MEK-ERK and JNK mitogen-activated protein kinases (MAPKs), their positive and negative regulators and a downstream effector C/EBPbeta. As in other cells, the abundance of VDR protein increases shortly after an exposure of HL60 cells to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2) D(3)). Other early events include a parallel upregulation of kinase suppressor of Ras (KSR-1) and the activation of the ERK MAPK pathway and data suggest that KSR-1 acts to amplify the signal provided by low concentrations of 1alpha,25(OH)(2) D(3). Maintenance of monocytic differentiation may be enhanced by JNK, but diminished by p38, MAPK signaling. Downstream, one of the targets of these pathways is C/EBPbeta, which can directly interact with the promoter for CD14, a gene characteristically expressed in monocytes. Importantly, in freshly obtained acute myeloid leukemia (AML)-M2 cells exposed to PRI-2191, a novel deltanoid with a modified side chain, upregulation of C/EBPbeta paralleled the induction of monocytic differentiation. These data provide a basis for the hypothesis that deltanoid-induced upregulation of C/EBPbeta bypasses the block to granulocytic differentiation in myeloid leukemia cells by redirecting the cells to monocytic differentiation.
维生素D衍生物（骨化二醇）在治疗髓系白血病方面具有潜在前景的证据越来越多，但目前对于实现这些抗肿瘤作用的确切机制的理解还不够深入。与实体瘤不同，在实体瘤中骨化二醇导致的生长迟缓似乎是由于抑制细胞增殖和通过凋亡促进细胞死亡，而骨化二醇对髓系白血病增殖的控制是通过诱导未成熟的髓单核细胞向功能性单核细胞分化来实现的。我们在此展示越来越多的证据表明，由维生素D受体（VDR）的骨化二醇激活引发并导致人髓母细胞性HL60细胞单核细胞分化的一条信号通路，包括MEK-ERK和JNK丝裂原活化蛋白激酶（MAPK）、它们的正负调节因子以及下游效应物C/EBPβ。与其他细胞一样，HL60细胞暴露于1α,25-二羟基维生素D3（1α,25(OH)2D3）后不久，VDR蛋白的丰度就会增加。其他早期事件包括Ras激酶抑制因子（KSR-1）的平行上调以及ERK MAPK信号通路的激活，数据表明KSR-1起到放大低浓度1α,25(OH)2D3提供的信号的作用。JNK可能会增强单核细胞分化的维持，但p38 MAPK信号会使其减弱。在下游，这些信号通路的靶点之一是C/EBPβ，它可以直接与CD14的启动子相互作用，CD14是一种在单核细胞中特异性表达的基因。重要的是，在新鲜获取的急性髓系白血病（AML）-M2细胞中，暴露于具有修饰侧链的新型骨化二醇PRI-2191后，C/EBPβ的上调与单核细胞分化的诱导平行。这些数据为以下假设提供了依据：骨化二醇诱导的C/EBPβ上调通过将细胞重定向至单核细胞分化，绕过了髓系白血病细胞中粒细胞分化的阻滞。
