Center for Molecular Prevention and Environmental Medicine, Department of Preventive Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259‑1193, Japan.
Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa 259‑1193, Japan.
Oncol Rep. 2018 Apr;39(4):1805-1812. doi: 10.3892/or.2018.6279. Epub 2018 Feb 23.
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.
肝细胞癌的预后极差。在癌组织中，癌细胞的异常增殖导致不成熟的血管网络形成的区域。由于癌细胞通过血流获得氧气供应，因此肿瘤的一部分会暴露于缺氧环境中。由于缺氧已知会严重降低现有抗癌药物的效果，因此必须确定治疗肝细胞癌的新有效治疗靶点。一般来说，自噬已被报道在癌细胞对缺氧的适应中发挥重要作用。然而，这一过程的具体作用和意义因癌症类型而异，需要在个体原发性肿瘤和细胞系中进行详细分析。在本研究中，我们检查了钴氯化物（一种模拟缺氧的试剂）诱导的肝细胞癌细胞中的自噬，目的是评估该过程作为潜在治疗靶点的有效性。我们观察到，钴氯化物处理以 AMPK 依赖性方式诱导自噬，包括细胞内质量控制机制。此外，在模拟缺氧条件下，自噬抑制剂（巴弗洛霉素和 LY294002）的处理导致显著的、高度选择性的细胞毒性和凋亡激活。在模拟缺氧条件下，AMPK 的敲低也显示出显著的细胞毒性。这些结果清楚地表明，自噬，特别是线粒体自噬，是由 AMPK 通路诱导的，当肝细胞癌细胞处于缺氧环境时，它在这些细胞适应这种环境中发挥重要作用。因此，自噬可能成为治疗肝细胞癌的有吸引力的治疗靶点。
