Hexokinase 2 Depletion Confers Sensitization to Metformin and Inhibits Glycolysis in Lung Squamous Cell Carcinoma
Hexokinase 2 Depletion Confers Sensitization to Metformin and Inhibits Glycolysis in Lung Squamous Cell Carcinoma
复制标题
己糖激酶 2 耗竭赋予二甲双胍敏感性并抑制肺鳞状细胞癌中的糖酵解
DOI：
10.3389/fonc.2020.00052
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发表时间：
2020-01-31
影响因子：
4.7
通讯作者：
Wu, Wenjuan
中科院分区：
文献类型：
--
作者：
Guo, Wenzheng;Kuang, Yanbin;Wu, Wenjuan
肺鳞状细胞癌（SCC）是一种高度侵袭性的肿瘤，由于缺乏特异性的突变靶点，目前尚无有效的靶向治疗。与肺腺癌（ADC）相比，据报道肺SCC利用更高水平的葡萄糖代谢来满足维持快速肿瘤生长所需的合成代谢和分解代谢需求。己糖激酶2（HK2）是一种催化葡萄糖代谢限速和第一个关键步骤的酶。在此，我们研究了HK2在肺SCC中的表达和作用。我们发现HK2在肺SCC中的表达显著更高，但在肺ADC或正常组织中没有。HK2缺失或抑制可通过激活AMPK信号通路降低mTORC 1活性，从而抑制糖酵解和肿瘤生长。此外，我们发现增加的氧呼吸速率补偿HK2消耗。因此，二甲双胍治疗显示出组合治疗价值，其导致体外和体内肺SCC凋亡的更大诱导。我们的研究表明，HK2耗竭联合二甲双胍可能是肺SCC治疗的一种新的有效策略。
Lung squamous cell carcinomas (SCCs) are highly aggressive tumors, and there is currently no effective targeted therapy owing to the lack of specific mutation targets. Compared with lung adenocarcinoma (ADCs), lung SCCs reportedly utilized higher levels of glucose metabolism to meet the anabolic and catabolic needs required to sustain rapid tumor growth. Hexokinase 2 (HK2) is an enzyme that catalyzes the rate-limit and first committed step in glucose metabolism. Here, we investigated the expression and effect of HK2 in lung SCCs. We found a significantly higher HK2 expression in lung SCCs, but not lung ADC or normal tissues. HK2 depletion or inhibition decreased the glycolysis and tumor growth via activating AMPK signaling pathway, which downregulated mTORC1 activity. Furthermore, we found an increased oxygen respiration rate compensating for HK2 depletion. Thus, metformin treatment showed combinatorial therapeutic value, which resulted in greater induction of lung SCC apoptosis in vitro and in vivo. Our study suggests that HK2 depletion in combination with metformin might be a novel effective strategy for lung SCCs therapy.