糖酵解
癌症研究
己糖激酶
mTORC1型
氧化磷酸化
二甲双胍
基因沉默
葡萄糖激酶
蛋白激酶B
磷酸化
化学
生物
细胞生物学
生物化学
内分泌学
新陈代谢
胰岛素
基因
作者
Dannielle C. DeWaal,Véronique Nogueira,Alexander R. Terry,Krushna C. Patra,Sang‐Min Jeon,Grace Guzman,Jennifer Au,Christopher P. Long,Maciek R. Antoniewicz,Nissim Hay
标识
DOI:10.1038/s41467-017-02733-4
摘要
Abstract Hepatocellular carcinoma (HCC) cells are metabolically distinct from normal hepatocytes by expressing the high-affinity hexokinase (HK2) and suppressing glucokinase (GCK). This is exploited to selectively target HCC. Hepatic HK2 deletion inhibits tumor incidence in a mouse model of hepatocarcinogenesis. Silencing HK2 in human HCC cells inhibits tumorigenesis and increases cell death, which cannot be restored by GCK or mitochondrial binding deficient HK2. Upon HK2 silencing, glucose flux to pyruvate and lactate is inhibited, but TCA fluxes are maintained. Serine uptake and glycine secretion are elevated suggesting increased requirement for one-carbon contribution. Consistently, vulnerability to serine depletion increases. The decrease in glycolysis is coupled to elevated oxidative phosphorylation, which is diminished by metformin, further increasing cell death and inhibiting tumor growth. Neither HK2 silencing nor metformin alone inhibits mTORC1, but their combination inhibits mTORC1 in an AMPK-independent and REDD1-dependent mechanism. Finally, HK2 silencing synergizes with sorafenib to inhibit tumor growth.
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