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Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1? pathway suppression.

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/HIF1? 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.

SUBMITTER: Weng ML

PROVIDER: S-EPMC7170903 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Weng Mei-Lin ML Chen Wan-Kun WK Chen Xiang-Yuan XY Lu Hong H Sun Zhi-Rong ZR Yu Qi Q Sun Peng-Fei PF Xu Ya-Jun YJ Zhu Min-Min MM Jiang Nan N Zhang Jin J Zhang Jian-Ping JP Song Yuan-Lin YL Ma Duan D Zhang Xiao-Ping XP Miao Chang-Hong CH Miao Chang-Hong CH

Nature communications 20200420 1

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 i ...[more]

PMID: 32313017

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Project description:BACKGROUND:Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers, including colorectal cancer. Recent years have witnessed the importance of metabolism transformation in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. Our previous studies demonstrated that KL played negative roles in colon cancer cell proliferation and metastasis. However, its role in the cancer cell reprogramming has seldom been reported. The aim of this study was to examine the role of KL in aerobic glycolysis in colorectal cancer. METHODS:Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and KL expression in colorectal cancer tissues. The impact of KL on glucose metabolism and its mechanisms were further validated in vitro and in vivo. RESULTS:Patients with lower KL expression exhibited higher 18F-FDG uptake (P?<?0.05), indicating that KL might participate in aerobic glycolysis regulation. In vitro assay by using colon cancer cell lines further supported this observation. By overexpressing KL in HTC116 and SW480 cells, we observed that the glycolysis was inhibited and the mitochondrial respiration increased, indicating that KL was a negative regulator of aerobic glycolysis. To seek for the underlying mechanisms, we tried to dig out the relation between KL and HIF1? signaling pathway, and found that KL negatively regulated HIF1? protein level and transcriptional activity. Western blot analysis showed that KL overexpression negatively regulated ERK pathway, and KL regulated aerobic glycolysis in part through its regulation of ERK/ HIF1? axis. CONCLUSIONS:Taken together, KL is a negative regulator of aerobic glycolysis and KL inhibited glucose metabolism transformation via the ERK/ HIF1? axis.

Project description:Osteosarcoma (OS) is a primary malignant tumor that occurs in bone, and mainly affects children and adolescents. C?type lectin domain family 3 member A (CLEC3A) is a member of the C?type lectin superfamily, which regulates various biological functions of cells. The present study aimed to identify the effects and related mechanisms of CLEC3A in the proliferation and chemosensitivity of OS cells. The expression of CLEC3A in OS was analyzed using the Gene Expression Omnibus data profile GSE99671, and its expression in OS samples was verified using reverse transcription?quantitative PCR (RT?qPCR) and immunohistochemical staining. The relationship between the expression of CLEC3A and clinical traits in patients with OS was also analyzed, including age, tumor size, TNM stage and lymph node metastasis. Cell Counting Kit?8 assays, colony formation assays and cell cycle distribution analysis were used to determine the roles of CLEC3A in the proliferation and chemosensitivity of OS cells. Finally, RT?qPCR and western blotting were used to demonstrate the relationship between CLEC3A and the AKT1/mTOR/hypoxia?inducible factor 1?? (HIF1?) pathway. Both the mRNA and protein expression levels of CLEC3A were increased in OS tissues compared with adjacent non?tumor tissues, and this was positively associated with TNM stage and lymph node metastasis. The genetic knockdown of CLEC3A with small interfering RNA decreased OS cell proliferation and colony formation, and induced G1 phase arrest, whereas the overexpression of CLEC3A increased OS cell proliferation and colony formation, and alleviated G1 phase arrest. The suppression of CLEC3A also promoted enhanced the chemosensitivity of OS cells to doxorubicin (DOX) and cisplatin (CDDP); it also inhibited the expression of AKT1, mTOR and HIF1?, further to the nuclear localization of HIF1?, and HIF1? target gene expression levels, including VEGF, GLUT1 and MCL1 were also decreased. Furthermore, treatment with the AKT activator SC79 blocked the inhibitory effects of CLEC3A silencing in OS cells. In conclusion, these findings suggested that CLEC3A may function as an oncogene in OS, and that the suppression of CLEC3A may inhibit OS cell proliferation and promote chemosensitivity through the AKT1/mTOR/HIF1? signaling pathway.

Dataset Information

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1? pathway suppression.

Publications

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

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