Alpha fetoprotein is a novel protein-binding partner for caspase-3 and blocks the apoptotic signaling pathway in human hepatoma cells
Alpha fetoprotein is a novel protein-binding partner for caspase-3 and blocks the apoptotic signaling pathway in human hepatoma cells
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甲胎蛋白是 caspase-3 的新型蛋白结合伴侣，可阻断人肝癌细胞中的凋亡信号通路
DOI：
10.1002/ijc.24272
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发表时间：
2009-06-15
影响因子：
6.4
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Li, Mengsen;Li, Hui;Li, Gang
虽然越来越多的证据表明甲胎蛋白(AFP)可能是肿瘤细胞生长的调节因子，但其确切机制仍不清楚。在目前的研究中，我们研究了胞浆AFP在caspase-3介导的细胞凋亡信号中的作用。我们的结果表明，肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的低丢失可提高caspase-8的活性，但不能提高caspase-3的活性。当细胞与全反式维甲酸(ATRA)或TRAIL共同作用时，Caspase-3在Bel 7402细胞胞浆中与AFP共定位并相互作用，并移位到细胞核内，与细胞发生凋亡有关。AFP能与caspase-3形成复合体，阻断caspase-8信号的向前传递。AFP的敲除增加了Bel 7402细胞对TRAIL的敏感性，从而触发了caspase-3信号转导。AFP与caspase-8之间没有分子间相互作用，AFP被敲除后caspase-8的活性也没有改变，表明AFP具有干扰细胞凋亡信号通路的选择性。将AFP基因导入HLE细胞(AFP阴性)，进一步证实了AFP对caspase-3的影响。我们得出结论，在产生AFP的肝癌中，ATRA或TRAIL耐药至少部分归因于细胞质AFP的高水平。因此，AFP基因沉默与ATRA/TRAIL联合治疗可能有利于提高这些药物对肿瘤的化疗效率。(C)2009年UICC
Although there is increasing evidence that alpha fetoprotein (AFP) may function as regulatory factor in the growth of tumor cells, the precise mechanism is still unclear. In the current study, we investigated the role of the cytoplasmic AFP in caspase-3-mediated signaling of apoptosis. Our results showed that low (loses of TNF-related apoptosis-inducing ligand (TRAIL) elevated the activity of caspase-8, but not caspase-3. Caspase-3 colocalized and interacted with AFP in the cytoplasm of Bel 7402 cells, and translocated into nuclei in association with the occurrence of apoptosis while cells were under cotreatment with all-trans retinoic acid (ATRA) or TRAIL. AFP was able to form complexes with caspase-3 and block onward transmission of signaling from caspase-8. Knockdown of AFP increased the sensitivity of Bel 7402 cells to TRAIL, and thereby, triggered caspase-3 signaling. No intermolecule interaction occurred between AFP and caspase-8, nor was caspase-8 activity altered after AFP knockdown, demonstrating the selectivity of AFP in interfering with the apoptotic signaling pathway. The effect of AFP on caspase-3 was further confirmed by transfection of the AFP gene into HLE cells (AFP negative). We conclude that ATRA or TRAIL resistance in AFP producing hepatoma is at least, in part, attributable to the high level of the cytoplasmic AFP. Therefore, it is possible that the combination of AFP gene silencing together with ATRA/TRAIL cotreatment will benefit the enhancement of the chemotherapeutic efficiency of these agents on tumors. (C) 2009 UICC