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TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells
Suli Lv1, Zongbiao Zhang2, Zhenyong Li1
1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet, cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall shed insight into cancer progression and benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. It remains unclear whether and how TFE3 responds to glucose starvation. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.
Insights
Kidney cancer cells resist glucose starvation via the TFE3-SLC36A1 pathway. This axis stabilizes TFE3, increasing amino acid transporter SLC36A1, which enhances cancer cell survival and therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Cancer cells exhibit high nutrient demands, particularly glucose.
- Targeting glucose metabolism, such as inhibiting glucose transporter GLUT1, is a cancer therapy strategy.
- Cancer cells can develop resistance to glucose starvation, a mechanism not fully understood.
Purpose of the Study:
- To investigate the role of transcription factor TFE3 in kidney cancer cell response to glucose starvation.
- To elucidate the molecular mechanisms by which TFE3 confers resistance to glucose deprivation.
- To identify novel therapeutic targets for enhancing sensitivity to glucose metabolism inhibitors.
Main Methods:
- Utilized kidney cancer cell models under physiologically relevant glucose concentrations.
- Investigated TFE3 protein stabilization via O-GlcNAcylation in response to glucose starvation.
- Performed unbiased functional genomic screening to identify TFE3 target genes.
- Assessed the role of SLC36A1 in cancer cell proliferation and starvation tolerance.
- Evaluated the combined effect of targeting TFE3 or SLC36A1 with GLUT1 inhibitors.
Main Results:
- Glucose starvation stabilizes TFE3 protein through increased O-GlcNAcylation.
- Identified lysosomal amino acid transporter SLC36A1 as a TFE3 target gene.
- SLC36A1 is overexpressed in kidney cancer, promoting mTOR activity and proliferation.
- Glucose starvation induces SLC36A1 via TFE3, enhancing cellular resistance to starvation.
- Inhibition of TFE3 or SLC36A1 increases sensitivity to GLUT1 inhibitors in kidney cancer cells.
Conclusions:
- A novel TFE3-SLC36A1 axis is identified that mediates kidney cancer cell resistance to glucose starvation.
- This axis involves TFE3 stabilization and subsequent induction of SLC36A1, promoting survival under nutrient-deprived conditions.
- Targeting the TFE3-SLC36A1 pathway represents a potential strategy to overcome therapeutic resistance in kidney cancer.
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