High dose of extracellular ATP switched autophagy to apoptosis in anchorage-dependent and anchorage-independent hepatoma cells
High dose of extracellular ATP switched autophagy to apoptosis in anchorage-dependent and anchorage-independent hepatoma cells
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高剂量细胞外 ATP 将贴壁依赖性和贴壁非依赖性肝癌细胞的自噬转变为凋亡
DOI：
10.1007/s11302-013-9369-0
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Han, Lihui
中科院分区：
文献类型：
--
作者：
Wei, Qing;Zhang, Ying;Han, Lihui
细胞外三磷酸腺苷（eATP）是嘌呤能信号的传递者，在肿瘤细胞的生长和死亡等生物学过程中起着重要的调节作用。大量eATP存在于快速生长的肿瘤中心和炎性肿瘤微环境中。肿瘤细胞在肿瘤微环境中可获得抗失巢凋亡和锚定独立性，进而引起转移性病变。如此高量的eATP是否对肿瘤微环境中的锚定和非锚定肿瘤细胞有任何影响尚未阐明，并在本研究中进行了研究。我们的数据表明，自噬有助于肝癌细胞在不超过1 mM的eATP处理下维持生存。只有当eATP浓度达到相对较高的水平（2.5 mM）时，细胞器才不能通过自噬进一步维持，发生凋亡和细胞死亡。在2.5 mM eATP处理的肝癌细胞中，AMP激活的蛋白激酶（AMPK）通路被显著激活，而mTOR信号通路被抑制，与细胞凋亡协调。进一步的研究表明，AMPK/mTOR轴在eATP处理下自噬介导的细胞存活和凋亡诱导的细胞死亡之间的平衡中起关键作用。这项工作提供了证据来解释肝癌细胞如何逃避eATP诱导的细胞毒性，以及提供了一个重要的线索，考虑有效的操作癌症。
Extracellular adenosine triphosphate (eATP) transduces purinergic signal and plays an important regulatory role in many biological processes, including tumor cell growth and cell death. A large amount of eATP exists in the fast-growing tumor center and inflammatory tumor microenvironment. Tumor cells could acquire anoikis resistance and anchorage independence in tumor microenvironment and further cause metastatic lesion. Whether such a high amount of eATP has any effect on the anchored and non-anchored tumor cells in tumor microenvironment has not been elucidated and is investigated in this study. Our data showed that autophagy helped hepatoma cells to maintain survival under the treatment of no more than 1 mM of eATP. Only when eATP concentration reached a relatively high level (2.5 mM), cell organelle could not be further maintained by autophagy, and apoptosis and cell death occurred. In hepatoma cells under treatment of 2.5 mM of eATP, an AMP-activated protein kinase (AMPK) pathway was dramatically activated while mTOR signaling pathway was suppressed in coordination with apoptosis. Further investigation showed that the AMPK/mTOR axis played a key role in tipping the balance between autophagy-mediated cell survival and apoptosis-induced cell death under the treatment of eATP. This work provides evidence to explain how hepatoma cells escape from eATP-induced cytotoxicity as well as offers an important clue to consider effective manipulation of cancer.