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

• Published in: Nature communications Vol. 11; no. 1; p. 1869
• Main Authors: Weng, Mei-lin, Chen, Wan-kun, Chen, Xiang-yuan, Lu, Hong, Sun, Zhi-rong, Yu, Qi, Sun, Peng-fei, Xu, Ya-jun, Zhu, Min-min, Jiang, Nan, Zhang, Jin, Zhang, Jian-ping, Song, Yuan-lin, Ma, Duan, Zhang, Xiao-ping, Miao, Chang-hong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/31; 13/89; 14/34; 14/63; 49; 59; 631/67/1504/1885; 631/67/2327; AKT protein; Animals; Anticancer properties; Antitumor activity; Cancer; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms - metabolism; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Crosstalk; Disease Models, Animal; Down-Regulation; Downstream effects; Farnesyl-diphosphate farnesyltransferase; Farnesyl-Diphosphate Farnesyltransferase - genetics; Farnesyl-Diphosphate Farnesyltransferase - metabolism; Farnesyltransferase; Fasting; Fasting - psychology; Female; Gene expression; Glucose; Glucose metabolism; Glycolysis; Glycolysis - physiology; Humanities and Social Sciences; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Malignancy; Metabolism; Mice, Inbred BALB C; Middle Aged; Molecular modelling; multidisciplinary; Proto-Oncogene Proteins c-akt - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Signaling; Synergism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor suppressor genes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15795-8

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. The molecular mechanisms underpinning how fasting inhibits tumourigenesis are not completely elucidated. Here, the authors show that fasting upregulates the cholesterogenic gene FDFT1 which leads to decreased AKT/mTOR/HIF1a signalling and glycolysis reduction in colorectal cancer.