The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions.
The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions.
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DOI：
10.1371/journal.pone.0137257
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Noshiro H
中科院分区：
文献类型：
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作者：
Tanaka T;Kitajima Y;Miyake S;Yanagihara K;Hara H;Nishijima-Matsunobu A;Baba K;Shida M;Wakiyama K;Nakamura J;Noshiro H
胃癌生长在低氧环境下。已知HIF-1α在低氧条件下控制线粒体中活性氧（ROS）的产生中起重要作用。我们先前在58 As 9胃癌细胞系中建立了HIF-1α敲低（KD）细胞和对照（SC）细胞。在这项研究中，我们发现，KD细胞，而不是SC细胞，诱导细胞凋亡的缺氧条件下（1%O2），由于过量生产的ROS。定量RT-PCR分析表明，HIF-1α调控了10个参与ROS调控机制（包括瓦尔堡效应、线粒体自噬、电子传递链修饰和ROS清除）的基因的表达。此外，葡萄糖加胰岛素（GI）处理促进葡萄糖摄入增强了细胞凋亡效应，并伴随着缺氧KD细胞中进一步产生活性氧。蛋白质印迹分析显示，葡萄糖和/或胰岛素处理提高了KD细胞中GLUT 1的膜表达，表明GI诱导的葡萄糖摄取是由细胞膜上GLUT 1易位增加介导的。最后，使用肿瘤异种移植模型评估HIF-1α敲低（KD）加GI的抗肿瘤作用，其中缺氧环境自然存在。结果，GI处理强烈抑制KD肿瘤的生长，从而与对照处理相比高度诱导细胞凋亡。相比之下，表达HIF-1α的SC肿瘤的生长不受GI处理的影响。综上所述，结果表明，HIF-1α抑制加GI可能是一种理想的治疗方法，因为在缺氧环境下生长的胃癌中，由于ROS稳态的破坏而特异性地诱导凋亡，而在有氧条件下的正常组织中则不诱导凋亡。
Gastric cancer grows under a hypoxic environment. HIF-1α is known to play an important role in controlling the production of reactive oxygen species (ROS) in the mitochondria under hypoxic conditions. We previously established HIF-1α knockdown (KD) cells and control (SC) cells in the 58As9 gastric cancer cell line. In this study, we revealed that KD cells, but not SC cells, induced apoptosis under conditions of hypoxia (1% O2) due to excessive production of ROS. A quantitative RT-PCR analysis demonstrated that the expressions of ten genes, which are involved in the control mechanisms of ROS (including the Warburg effect, mitophagy, electron transport chain [ETC] modification and ROS scavenging), were regulated by HIF-1α. Moreover, the promotion of glucose uptake by glucose plus insulin (GI) treatment enhanced the apoptotic effect, which was accompanied by further ROS production in hypoxic KD cells. A Western blot analysis showed that the membranous expression of GLUT1 in KD cells was elevated by glucose and/or insulin treatments, indicating that the GI-induced glucose uptake is mediated by the increased translocation of GLUT1 on the cell membrane. Finally, the anti-tumor effect of HIF-1α knockdown (KD) plus GI was evaluated using a tumor xenograft model, where a hypoxic environment naturally exists. As a result, the GI treatment strongly inhibited the growth of the KD tumors whereby cell apoptosis was highly induced in comparison to the control treatment. In contrast, the growth of the SC tumors expressing HIF-1α was not affected by the GI treatment. Taken together, the results suggest that HIF-1α inhibition plus GI may be an ideal therapy, because the apoptosis due to the destruction of ROS homeostasis is specifically induced in gastric cancer that grows under a hypoxic environment, but not in the normal tissue under the aerobic conditions.