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野生型 IDH2 通过 HIF1α 促进肺癌中的瓦博格效应和肿瘤生长。

Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer.

机构信息

Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, China.

Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha 410078, China.

出版信息

Theranostics. 2018 Jul 16;8(15):4050-4061. doi: 10.7150/thno.21524. eCollection 2018.

DOI:10.7150/thno.21524
PMID:30128035
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6096397/
Abstract

Hotspot mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) have been studied in several cancers. However, the function of wild-type IDH2 in lung cancer and the mechanism of its contribution to growth of cancer cells remain unknown. Here, we explored the role and mechanism of wild-type IDH2 in promoting growth of lung cancer. Information regarding genomic and clinical application focusing on IDH2 in cancer was examined in several databases of more than 1,000 tumor samples. IDH2 expression was assessed by immunohistochemistry in tissues from lung cancer patients. The biological functions of IDH2 were evaluated by using cell-based assays and xenograft mouse models. Here we reported that wild-type IDH2 is up-regulated and is an indicator of poor survival in lung cancer and several other cancers. Targeting with shRNA resulted in decreased HIF1α expression, leading to the attenuation of lung cancer cell proliferation and tumor growth. Treatment of lung cancer cells with AGI-6780 (a small molecule inhibitor of IDH2), PX-478 (an inhibitor of HIF1α) or incubation with octyl-α-KG inhibited lung cancer cell proliferation. IDH2 promotes the Warburg effect and lung cancer cell growth, which is mediated through HIF1α activation followed by decreased α-KG. Therefore, IDH2 could possibly serve as a novel therapeutic target for lung cancer.

摘要

IDH1 和 IDH2（异柠檬酸脱氢酶 1 和 2）的热点突变已在多种癌症中进行了研究。然而，野生型 IDH2 在肺癌中的功能及其对癌细胞生长的贡献机制尚不清楚。在这里，我们探讨了野生型 IDH2 在促进肺癌生长中的作用和机制。

我们在超过 1000 个肿瘤样本的多个数据库中研究了 IDH2 在癌症中的基因组和临床应用信息。通过免疫组织化学检测肺癌患者组织中的 IDH2 表达。通过细胞基础检测和异种移植小鼠模型评估 IDH2 的生物学功能。

在这里，我们报告野生型 IDH2 在肺癌和其他几种癌症中上调，并且是不良生存的指标。用 shRNA 靶向 IDH2 导致 HIF1α 表达降低，从而减弱肺癌细胞的增殖和肿瘤生长。用 AGI-6780（IDH2 的小分子抑制剂）、PX-478（HIF1α 的抑制剂）或 octyl-α-KG 孵育处理肺癌细胞可抑制肺癌细胞的增殖。

IDH2 通过激活 HIF1α 促进Warburg 效应和肺癌细胞生长，从而导致α-KG 减少。因此，IDH2 可能成为肺癌的新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a05/6096397/ed7afceeceb5/thnov08p4050g006.jpg
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