过剩1
癌症研究
mTORC1型
坦克结合激酶1
自噬
信号转导
生物
细胞生物学
葡萄糖摄取
内分泌学
MAPK/ERK通路
生物化学
PI3K/AKT/mTOR通路
细胞凋亡
MAP激酶激酶激酶
胰岛素
作者
Diyuan Zhou,Yizhou Yao,Liang Zong,Guoqiang Zhou,Ming Feng,Junjie Chen,Ganggang Liu,Guoliang Chen,Kang Sun,Heng‐Chen Yao,Yu Liu,Xinyu Shi,Weigang Zhang,Bo Shen,Qingliang Tai,Guanting Wu,Liang Sun,Wenqing Hu,Xinguo Zhu,Songbing He
摘要
Intestinal inflammation is a vital precipitating factor of colorectal cancer (CRC), but the underlying mechanisms are still elusive. TANK-binding kinase 1 (TBK1) is a core enzyme downstream of several inflammatory signals. Recent studies brought the impacts of TBK1 in malignant disease to the forefront, we found aberrant TBK1 expression in CRC is correlated with CRC progression. TBK1 inhibition impaired CRC cell proliferation, migration, drug resistance and tumor growth. Bioinformatic analysis and experiments in vitro showed overexpressed TBK1 inhibited mTORC1 signaling activation in CRC along with elevated GLUT1 expression without inducing GLUT1 translation. TBK1 mediated mTORC1 inhibition induces intracellular autophagy, which in turn decreasing GLUT1 degradation. As a rescue, blocking of autophagosome and retromer respectively via autophagy-related gene 7 (ATG7) or TBC1 Domain Family Member 5 (TBC1D5) silence diminished the regulation of TBK1 to GLUT1. GLUT1 staining presented that TBK1 facilitated GLUT1 membrane translocation which subsequently enhanced glucose consumption. Inhibitor of TBK1 also decreased GLUT1 expression which potentiated drug-sensitivity of CRC cell. Collectively, TBK1 facilitates glucose consumption for supporting CRC progression via initiating mTORC1 inhibition induced autophagy which decreases GLUT1 degradation and increases GLUT1 membrane location. The adaptive signaling cascade between TBK1 and GLUT1 proposes a new strategy for CRC therapy.
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