Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression

Mei-lin Weng, Wan-kun Chen, Xiang-yuan Chen, Hong Lu, Zhi-rong Sun, Qi Yu, Peng-fei Sun, Ya-jun Xu, Min-min Zhu, Nan Jiang, Jin Zhang, Jian-ping Zhang, Yuan-lin Song, Duan Ma (), Xiao-ping Zhang () and Chang-hong Miao ()
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Mei-lin Weng: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Wan-kun Chen: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Xiang-yuan Chen: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Hong Lu: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Zhi-rong Sun: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Qi Yu: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Peng-fei Sun: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Ya-jun Xu: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Min-min Zhu: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Nan Jiang: Fudan University
Jin Zhang: Fudan University
Jian-ping Zhang: Fudan University; Department of Nuclear Medicine, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University
Yuan-lin Song: Zhongshan Hospital, Fudan University
Duan Ma: Fudan University
Xiao-ping Zhang: Tongji University School of Medicine
Chang-hong Miao: Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

Date: 2020
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DOI: 10.1038/s41467-020-15795-8

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