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SMAD4通过激活ARHGAP10，经由PI3K/AKT/HK2信号通路抑制卵巢癌中的糖酵解。

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10.

作者信息

Wu Kui, Gong Wei, Sun Huanmei, Li Wenjiao, Chen Li, Duan Yingchun, Zhu Jianlong, Zhang Hu, Ke Huihui

机构信息

Department of Obstetrics and Gynecology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, PR China.

出版信息

Cancer Rep (Hoboken). 2024 Jan 17;7(2):e1976. doi: 10.1002/cnr2.1976.

DOI:10.1002/cnr2.1976
PMID:38230565
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10849991/
Abstract

BACKGROUND

ARHGAP10 is a tumor-suppressor gene related to ovarian cancer (OC) progression; however, its specific mechanism is unclear.

AIMS

To investigate the effect of ARHGAP10 on OC cell migration, invasion, and glycolysis.

METHODS AND RESULTS

Quantitative real-time PCR (qRT-PCR) quantified mRNA and protein expressions of AKT, p-AKT, HK2, and SMAD4 were tested by Western blot. EdU, Wound healing, and Transwell assay were utilized to evaluate OC cell proliferation, migration, and invasion. We used a Seahorse XF24 Extracellular Flux Analyzer to monitor cellular oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Chromatin immunoprecipitation (ChIP) was used to analyze the transcriptional regulation of ARHGAP10 by SMAD4. ARHGAP10 expression in OC tissues was detected by immunohistochemistry. Our results showed that ARHGAP10 expression was negatively related to lactate levels in human OC tissues. ARHGAP10 overexpression can inhibit the migration, proliferation, and invasion of OC cells, and this function can be blocked by 2-Deoxy-D-glucose. Moreover, we found that ARHGAP10 expression can be rescued with the AKT inhibitor LY294002.

CONCLUSIONS

This study revealed that the antitumor effects of ARHGAP10 in vivo and in vitro possibly suppress oncogenic glycolysis through the PI3K/AKT/HK2-regulated glycolysis metabolism pathway.

摘要

背景

ARHGAP10是一种与卵巢癌（OC）进展相关的肿瘤抑制基因；然而，其具体机制尚不清楚。

目的

研究ARHGAP10对OC细胞迁移、侵袭和糖酵解的影响。

方法与结果

采用定量实时PCR（qRT-PCR）定量分析mRNA，通过蛋白质免疫印迹法检测AKT、p-AKT、HK2和SMAD4的蛋白表达。利用EdU、伤口愈合实验和Transwell实验评估OC细胞的增殖、迁移和侵袭能力。使用海马XF24细胞外流量分析仪监测细胞耗氧率（OCR）和细胞外酸化率（ECAR）。采用染色质免疫沉淀（ChIP）分析SMAD4对ARHGAP10的转录调控。通过免疫组织化学检测OC组织中ARHGAP10的表达。我们的结果表明，ARHGAP10的表达与人类OC组织中的乳酸水平呈负相关。ARHGAP10过表达可抑制OC细胞的迁移、增殖和侵袭，且该功能可被2-脱氧-D-葡萄糖阻断。此外，我们发现使用AKT抑制剂LY294002可恢复ARHGAP10的表达。

结论

本研究表明，ARHGAP10在体内和体外的抗肿瘤作用可能是通过PI3K/AKT/HK2调节的糖酵解代谢途径抑制致癌糖酵解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/f765831d8e2d/CNR2-7-e1976-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/14032f1a6434/CNR2-7-e1976-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/d4b70c2fa396/CNR2-7-e1976-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/68ce81f9c2a4/CNR2-7-e1976-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/72c2f3eb0986/CNR2-7-e1976-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/f765831d8e2d/CNR2-7-e1976-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/14032f1a6434/CNR2-7-e1976-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/d4b70c2fa396/CNR2-7-e1976-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/68ce81f9c2a4/CNR2-7-e1976-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/72c2f3eb0986/CNR2-7-e1976-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b35c/10849991/f765831d8e2d/CNR2-7-e1976-g002.jpg

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TNFα and IFNγ rapidly activate PI3K-AKT signaling to drive glycolysis that confers mesenchymal stem cells enhanced anti-inflammatory property.TNFα 和 IFNγ 可迅速激活 PI3K-AKT 信号通路，促进糖酵解，赋予间充质干细胞更强的抗炎特性。
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