Klotho negatively regulated aerobic glycolysis in colorectal cancer via ERK/HIF1α axis.
Klotho negatively regulated aerobic glycolysis in colorectal cancer via ERK/HIF1α axis.
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Klotho 通过 ERK/HIF1 α 轴负调节结直肠癌的有氧糖酵解
DOI：
10.1186/s12964-018-0241-2
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发表时间：
2018-06-08
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Li Q;Li Y;Liang L;Li J;Luo D;Liu Q;Cai S;Li X
Klotho（KL）最初被表征为衰老抑制基因，并且已被鉴定为多种癌症（包括结肠直肠癌）中的肿瘤抑制基因。近年来，代谢转化在癌细胞恶性肿瘤维持中的重要性已被证实。异常的癌细胞代谢被认为是癌症的标志。我们前期的研究表明KL对结肠癌细胞的增殖和转移具有负性作用。然而，其在癌细胞重编程中的作用却很少报道。本研究的目的是研究KL在大肠癌有氧糖酵解中的作用。结合术前PET/CT扫描获得的最大标准化摄取值（SUVmax）和免疫组化染色，分析SUVmax与KL在结直肠癌组织中表达的相关性。KL对糖代谢的影响及其机制在体内外进一步验证。KL表达水平越低，18F-FDG摄取率越高（P < 0.05），提示KL可能参与有氧糖酵解调节。使用结肠癌细胞系的体外测定进一步支持了这一观察结果。通过在HTC116和SW 480细胞中过表达KL，我们观察到糖酵解被抑制，线粒体呼吸增加，表明KL是有氧糖酵解的负调节剂。为了探讨其可能的作用机制，我们试图挖掘KL与HIF 1 α信号通路的关系，发现KL负调控HIF 1 α的蛋白水平和转录活性。Western blot分析显示KL过表达负性调节ERK通路，KL部分通过调节ERK/HIF 1 α轴调节有氧糖酵解。总之，KL是有氧糖酵解的负调节剂，KL通过ERK/HIF 1 α轴抑制葡萄糖代谢转化。本文的在线版本（10.1186/s12964-018-0241-2）包含补充材料，可供授权用户使用。
Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers, including colorectal cancer. Recent years have witnessed the importance of metabolism transformation in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. Our previous studies demonstrated that KL played negative roles in colon cancer cell proliferation and metastasis. However, its role in the cancer cell reprogramming has seldom been reported. The aim of this study was to examine the role of KL in aerobic glycolysis in colorectal cancer. Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and KL expression in colorectal cancer tissues. The impact of KL on glucose metabolism and its mechanisms were further validated in vitro and in vivo. Patients with lower KL expression exhibited higher 18F-FDG uptake (P < 0.05), indicating that KL might participate in aerobic glycolysis regulation. In vitro assay by using colon cancer cell lines further supported this observation. By overexpressing KL in HTC116 and SW480 cells, we observed that the glycolysis was inhibited and the mitochondrial respiration increased, indicating that KL was a negative regulator of aerobic glycolysis. To seek for the underlying mechanisms, we tried to dig out the relation between KL and HIF1α signaling pathway, and found that KL negatively regulated HIF1α protein level and transcriptional activity. Western blot analysis showed that KL overexpression negatively regulated ERK pathway, and KL regulated aerobic glycolysis in part through its regulation of ERK/ HIF1α axis. Taken together, KL is a negative regulator of aerobic glycolysis and KL inhibited glucose metabolism transformation via the ERK/ HIF1α axis. The online version of this article (10.1186/s12964-018-0241-2) contains supplementary material, which is available to authorized users.
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