Arsenic trioxide cooperates with all trans retinoic acid to enhance mitogen-activated protein kinase activation and differentiation in PML-RARalpha negative human myeloblastic leukemia cells.
Arsenic trioxide cooperates with all trans retinoic acid to enhance mitogen-activated protein kinase activation and differentiation in PML-RARalpha negative human myeloblastic leukemia cells.
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DOI：
10.3109/10428194.2010.501535
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发表时间：
2010-09
影响因子：
2.6
通讯作者：
Yen A
中科院分区：
文献类型：
--
作者：
Nayak S;Shen M;Bunaciu RP;Bloom SE;Varner JD;Yen A
三氧化二砷 (ATO) 协同促进视黄酸 (RA) 诱导的 HL-60 成髓细胞白血病细胞（一种 PML-RARα 阴性细胞系）的分化。在 PML-RARα 阳性髓系白血病细胞中，已知 ATO 会导致 PML-RARα 降解，随后诱导髓系分化。现在我们发现ATO本身并不引起PML-RARα阴性HL-60细胞的分化，但增强了RA引起分化的能力。已知 RA 诱导的 HL-60 细胞分化是由诱导的过度活跃/持续的 MAPK 信号推动的。 ATO 增强了 RA 诱导的 RAF/MEK/ERK 轴信号传导和 CD11b 的表达，CD11b 是一种整合素受体，是骨髓分化标记物。 p47PHOX（呼吸爆发机制和诱导氧化代谢的组成部分）、功能分化标记物也得到增强。然而，ATO 不会增强 RA 诱导的 CD38 表达（一种早期细胞表面分化标记物）。 ATO 增强了 RA 诱导的群体生长迟缓，但没有细胞凋亡或增强的 G1/0 生长停滞的证据。但与 RA 相比，ATO 加 RA 显示 pAKT 降低，表明总体生物合成/代谢迟缓对 ATO 导致的明显增强的生长迟缓具有重要影响。总之，我们的结果表明，ATO 可以通过促进 MAPK 信号传导且不依赖于 PML-RARα 来增强 RA 引起髓系白血病细胞分化的作用。
Arsenic trioxide (ATO) synergistically promotes retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells, a PML-RARα negative cell line. In PML-RARα positive myeloid leukemia cells, ATO is known to cause degradation of PML-RARα with subsequent induced myeloid differentiation. We find now that ATO by itself does not cause differentiation of the PML-RARα negative HL-60 cells, but enhances RA’s capability to cause differentiation. RA-induced differentiation of HL-60 cells is known to be propelled by an induced hyperactive/persistent MAPK signal. ATO augmented RA induced RAF/MEK/ERK axis signaling and expression of CD11b, an integrin receptor that is a myeloid differentiation marker. p47PHOX, a component of the respiratory burst machinery and inducible oxidative metabolism, functional differentiation marker were also enhanced. However, ATO did not enhance RA-induced CD38 expression, an early cell surface differentiation marker. ATO enhanced RA-induced population growth retardation without evidence of apoptosis or an enhanced G1/0 growth arrest. But compared to RA, ATO plus RA showed reduced pAKT, suggesting that an overall biosynthetic/metabolic retardation was seminal to the apparent enhanced growth retardation due to ATO. In sum, our results indicate that ATO can augment action of RA in causing differentiation of myeloid leukemia cells through promoting MAPK signaling and independent of PML-RARα.