Apoptosis and tumor cell death in response to HAMLET (Human α-lactalbumin made lethal to tumor cells)
Apoptosis and tumor cell death in response to HAMLET (Human α-lactalbumin made lethal to tumor cells)
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DOI：
10.1007/978-0-387-74087-4_8
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Svanborg, Catharina
中科院分区：
文献类型：
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作者：
Hallgren, Oskar;Aits, Sonja;Svanborg, Catharina
HAMLET(人α-乳清蛋白对肿瘤细胞致死)是一种从母乳中提取的分子复合体，它通过类似于细胞程序性死亡的过程杀死肿瘤细胞。该复合体由部分未折叠的乳清蛋白和油酸组成，蛋白质和脂肪酸都是细胞死亡所必需的。哈姆雷特在体外具有广泛的抗肿瘤活性，在人胶质母细胞瘤大鼠异种移植模型、皮肤乳头状瘤患者和膀胱癌患者中的治疗效果已在体内得到证实。然而，肿瘤细胞死亡的机制仍不清楚。在遇到肿瘤细胞后，哈姆雷特立即侵入细胞，导致线粒体膜去极化，细胞色素c释放，磷脂酰丝氨酸暴露，半胱氨酸酶反应降低。部分细胞发生以凋亡为特征的形态变化，但抑制caspase不能挽救细胞，bcl2过表达或P53状态改变不影响肿瘤细胞对哈姆雷特的敏感性。哈姆雷特还创造了一种未折叠的蛋白质超载状态，并激活了20S蛋白酶体，这导致了细胞死亡。同时，Hamlet转位到肿瘤细胞核，在那里与组蛋白的高亲和力相互作用会导致染色质破坏、转录丢失和核凝集。死亡的细胞也表现出与巨型自噬相容的形态变化，最近的研究表明，巨型自噬参与了对哈姆雷特的细胞死亡反应。结果表明，哈姆雷特就像多头的九头蛇一样，可能与几个关键的细胞器相互作用，从而平行地激活几种形式的细胞死亡。这种复杂性可能是肿瘤细胞的快速死亡反应和哈姆雷特广泛的抗肿瘤活性的基础。
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded ot-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.