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首页> 外文期刊>Cell cycle >AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells.
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AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells.

机译:AKT途径被1,25-二羟基维生素D3激活,并在分化HL60细胞中参与其抗凋亡作用和细胞周期控制。

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Differentiation therapy for cancer is a developing treatment modality that is based on the anti-proliferative effects associated with differentiation of the malignant cells. 1,25-dihydroxyvitamin D(3) (1,25D) and its analogs are currently being evaluated clinically, alone or in combination with other agents, for treatment of several neoplastic diseases, but their usefulness as single agents may be limited by the enhancement of cell survival in some cell types exposed to 1,25D. In this study we evaluated the role of AKT signaling pathway, known to be anti-apoptotic in diverse cell types, in enhancing the survival of human leukemia HL60 cells induced to differentiate with 1,25D. We found that the phosphorylation and activity of AKT, as well as of its downstream targets, are increased after the exposure to 1,25D. Treatment of HL60 cells with PI3K inhibitors LY294002 and Wortmannin, which decrease the activity of the AKT pathway, induced apoptosis, but this effect was reduced in cells simultaneously treated with 1,25D. Interestingly, LY294002 and Wortmannin also accentuated the 1,25D-induced G(1) to S phase cell cycle block in HL60 cells, and this was associated with an increased expression of p27Kip1. Thus, a combination of 1,25D with inhibitors of AKT pathway is strongly anti-proliferative and should therefore be considered for differentiation therapy of myeloid leukemia.
机译:癌症的分化疗法是一种发展中的治疗方法,其基于与恶性细胞分化相关的抗增殖作用。 1,25-dihydroxyvitamin D(3)(1,25D)及其类似物目前正在临床上单独或与其他药物联合用于治疗多种肿瘤疾病的评估,但由于增强作用,它们作为单一药物的用途可能受到限制暴露于1,25D的某些细胞类型中的细胞存活率在这项研究中,我们评估了AKT信号通路(在多种细胞类型中均具有抗凋亡作用)在增强人白血病HL60细胞(以1,25D诱导分化)的存活中的作用。我们发现,暴露于1,25D后,AKT及其下游靶标的磷酸化和活性增加。用PI3K抑制剂LY294002和Wortmannin处理HL60细胞会降低AKT途径的活性,从而诱导细胞凋亡,但是在同时用1,25D处理的细胞中这种作用减弱了。有趣的是,LY294002和Wortmannin还强调了HL60细胞中1,25D诱导的G(1)至S期细胞周期阻滞,这与p27Kip1的表达增加有关。因此,1,25D与AKT途径抑制剂的组合具有很强的抗增殖作用,因此应考虑用于髓样白血病的分化治疗。

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