Autophagy-mediated adaptation of hepatocellular carcinoma cells to hypoxia-mimicking conditions constitutes an attractive therapeutic target
Autophagy-mediated adaptation of hepatocellular carcinoma cells to hypoxia-mimicking conditions constitutes an attractive therapeutic target
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DOI：
10.3892/or.2018.6279
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发表时间：
2018-04-01
期刊：
影响因子：
4.2
通讯作者：
Tatemichi, Masayuki
中科院分区：
文献类型：
--
作者：
Owada, Satoshi;Endo, Hitoshi;Tatemichi, Masayuki
肝细胞癌预后极差。在癌性肝组织中，癌细胞的异常增殖导致形成未成熟血管网络的区域的产生。由于氧气是通过血流供应给癌组织的，因此肿瘤的一部分暴露于缺氧条件下。由于已知缺氧会严重降低现有抗癌药物的有效性，因此必须确定新的有效治疗靶点用于治疗肝细胞癌。一般来说，自噬已被报道在癌细胞对缺氧的适应中起重要作用。然而，这一过程的确切作用和意义因癌症类型而异，需要对单个原发性肿瘤和细胞系进行详细分析。在本研究中，我们研究了自噬诱导氯化钴，缺氧模拟剂，在肝细胞癌细胞的目的是评估这一过程的有效性作为一个潜在的治疗靶点。我们观察到，氯化钴治疗诱导自噬，包括细胞内的质量控制机制，在AMPK依赖性的方式。此外，用自噬抑制剂（巴弗洛霉素和LY294002）处理导致在低氧模拟条件下显著的、高选择性的细胞毒性和凋亡激活。AMPK的敲低还揭示了在低氧模拟条件下的显著细胞毒性。这些结果清楚地表明，自噬，特别是线粒体自噬，诱导AMPK通路时，肝细胞癌细胞受到缺氧条件下，并发挥了重要作用，这些细胞的适应，这些条件。因此，自噬可能成为治疗肝细胞癌的一个有吸引力的治疗靶点。
Hepatocellular carcinoma has extremely poor prognosis. In cancerous liver tissues, aberrant proliferation of cancer cells leads to the creation of an area where an immature vascular network is formed. Since oxygen is supplied to cancer tissues through the bloodstream, a part of the tumor is exposed to hypoxic conditions. As hypoxia is known to severely reduce the effectiveness of existing anticancer agents, novel valid therapeutic targets must be identified for the treatment of hepatocellular carcinoma. Generally, autophagy has been reported to play an important role in the adaptation of cancer cells to hypoxia. However, the exact role and significance of this process vary depending on the cancer type, requiring detailed analysis in individual primary tumors and cell lines. In the present study, we examined autophagy induced by cobalt chloride, a hypoxia-mimicking agent, in hepatocellular carcinoma cells with the aim to evaluate the validity of this process as a potential therapeutic target. We observed that treatment with cobalt chloride induced autophagy, including the intracellular quality control mechanism, in an AMPK-dependent manner. Furthermore, treatment with autophagy inhibitors (bafilomycin and LY294002) resulted in significant, highly-selective cytotoxicity and apoptosis activation under hypoxia-mimicking conditions. The knockdown of AMPK also revealed significant cytotoxicity in hypoxia-mimicking conditions. These results clearly demonstrated that autophagy, especially mitophagy, was induced by the AMPK pathway when hepatocellular carcinoma cells were subjected to hypoxic conditions and played an important role in the adaptation of these cells to such conditions. Thus, autophagy may constitute an attractive therapeutic target for the treatment of hepatocellular carcinoma.