创作:Lexi 审核:Lexi 2019年09月02日
  • p63和SOX2通过SLC2A1内源增强子反式激活驱动GLUT1表达上调;
  • 由GLUT1表达上调调控的葡萄糖流入为抗氧化剂(如NADPH和GSH)生产提供原料,增强鳞状细胞癌(SCC)抗氧化能力,从而促进癌细胞生存;
  • 利用生酮饮食或SGLT2抑制剂抑制肾脏葡萄糖再吸收等方式系统性限制葡萄糖可同时靶向重要的代谢及致癌相关通路;
  • 血糖降低可导致血胰岛素水平降低,并抑制SCC细胞中PI3K/AKT通路;
  • 高随机性血糖量与SCC患者更坏的预后相关。
鳞状细胞癌(SCC)起源于不同的解剖学位点,因可选择的治疗手段较少而造成较高的癌症死亡率。最新发表在Cell Reports上的研究报道了过度活跃的GLUT1介导的葡萄糖内流导致SCC对葡萄糖的过度依赖及其内在机制。
Cell Reports [IF:8.109]

p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas



2019-08-13, Article

Abstract & Authors:展开

Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction.

First Authors:
Meng-Hsiung Hsieh

Correspondence Authors:
Jung-whan Kim

All Authors:
Meng-Hsiung Hsieh,Joshua H Choe,Jashkaran Gadhvi,Yoon Jung Kim,Marcus A Arguez,Madison Palmer,Haleigh Gerold,Chance Nowak,Hung Do,Simbarashe Mazambani,Jordan K Knighton,Matthew Cha,Justin Goodwin,Min Kyu Kang,Ji Yun Jeong,Shin Yup Lee,Brandon Faubert,Zhenyu Xuan,E Dale Abel,Claudio Scafoglio,David B Shackelford,John D Minna,Pankaj K Singh,Vladimir Shulaev,Leonidas Bleris,Kenneth Hoyt,James Kim,Masahiro Inoue,Ralph J DeBerardinis,Tae Hoon Kim,Jung-whan Kim