期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 18, 期 8, 页码 3374-3389出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.70742
关键词
TBK1; GLUT1; Colorectal cancer; mTORC1; Autophagy
资金
- National Natural Science Foundation of China [82103362]
- Natural Science Foundation of Jiangsu Province of China [BK20191172]
- Project of Key Laboratory of Clinical Pharmacy of Jiangsu Province of China [XZSYSKF2020027]
- Project of Gusu Medical Key Talent of Suzhou City of China [GSWS2020005]
- Project of Science and Technology Development Plan of Suzhou City of China [SYS2019007, SYS2019050]
- Project of New Pharmaceutics and Medical Apparatuses of Suzhou City of China [SLJ2021007]
Intestinal inflammation is a key factor in the development of colorectal cancer (CRC). Recent studies have shown that TBK1, a downstream enzyme of inflammatory signals, plays a role in CRC progression by inhibiting mTORC1 signaling and increasing GLUT1 expression and translocation, leading to enhanced glucose consumption. This finding provides a new therapeutic strategy for CRC.
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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