A natural small molecule induces megakaryocytic differentiation and suppresses leukemogenesis through activation of PKC delta/ERK1/2 signaling pathway in erythroleukemia cells
A natural small molecule induces megakaryocytic differentiation and suppresses leukemogenesis through activation of PKC delta/ERK1/2 signaling pathway in erythroleukemia cells
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天然小分子通过激活红白血病细胞中的 PKC delta/ERK1/2 信号通路诱导巨核细胞分化并抑制白血病发生
DOI：
10.1016/j.biopha.2019.109265
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发表时间：
2019
影响因子：
7.5
通讯作者：
Hao Xiaojiang
中科院分区：
文献类型：
--
作者：
Yang Jue;Qiu Jianfei;Hu Yong;Zhang Yongqiang;Chen Li;Long Qun;Chen Juan;Song Jingrui;Rao Qing;Li Yanmei;Gu Wei;Hao Xiaojiang
山奈酚-3-O-鼠李糖苷（KOR）具有抗癌、抗炎和抗菌等多种作用。然而，从青钱柳叶中分离的KOR及其类似物在抗红白血病中的潜在作用尚不清楚。从青钱柳（Cyclocarya paliurus）叶片中分离得到KOR及其类似物山奈酚-3-O-（4″-O-acetyl-a-L-rhamnopyranoside）（KLR）和山奈酚-3-O-α-L-（4″-E-p-coumaroyl）rhamnoside）（KCR）。细胞活力测定显示KCR具有良好的抗红白血病活性。我们观察到KCR不仅使HEL和K562细胞的G2期细胞比例和凋亡细胞比例显著增加，而且通过流式细胞仪检测还可诱导细胞向巨核细胞分化，表明KCR可能通过诱导分化介导的凋亡和细胞周期阻滞来抑制细胞增殖。KCR处理后，PKCδ和ERK 1/2的磷酸化水平明显升高，GATA 1的表达明显增加。总之，这些结果表明，KCR诱导巨核细胞分化和抑制白血病发生至少部分通过激活PKCδ/ERK 1/2信号通路。KCR也可能作为一种有前途的天然化合物用于治疗人类红白血病。
Kaempferol-3-O-rhamnoside (KOR) has multiple potency involved in anti-cancer, anti-inflammatory and antibacterial actions. However, the potential roles of KOR and the analogues isolated from the leaves ofCyclocarya paliurusin anti-erythroleukemia remain unclear. In the present study, KOR and the two analogues (Kaempferol-3-O-(4″-O-acetyl-a-L-rhamnopyranoside) (KLR) and (kaempferol-3-O-α-L-(4″-E-p-coumaroyl) rhamnoside) (KCR) were isolated from leaves ofCyclocarya paliurus. Cell viability assay showed that KCR exerted an excellent anti-erythroleukemia activity. We observed that KCR not only significantly increased the percentage of G2 phase and apoptotic cells compared with control group, but also induced megakaryocytic differentiation in HEL and K562 cells by flow cytometry, indicating that KCR might inhibit cell proliferation through inducing differentiation-mediated apoptosis and cell cycle arrest. Mechanism investigation revealed that KCR treatment obviously increased phosphorylation levels of PKCδ and ERK1/2 as well as GATA1 expression. Taken together, these findings demonstrate that KCR induces megakaryocytic differentiation and suppresses leukemogenesis at least partly through activation of PKCδ/ERK1/2 signaling pathway in erythroleukemia cells. KCR may also serve as a promising natural compound for human erythroleukemia treatment.