The FBW7-KLF2 axis regulates endothelial functions.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC3674388 | biostudies-other | 2013 Jun
REPOSITORIES: biostudies-other
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Project description:FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that FBW7 substantially decreased 18F-fluorodeoxyglucose uptake in xenograft tumors. Mechanistically, FBW7 inhibited glucose metabolism via c-Myc/TXNIP axis. But in these studies, we observed FBW7 down-regulated genes were widely involved in redox reaction and lipid metabolism. Here we reanalyzed previous gene expression profiling and conducted targeted cell metabolites analysis. Results revealed that FBW7 regulated lipid peroxidation and promoted ferroptosis, a non-apoptotic form of cell death. Mechanistically, we found FBW7 inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis, which was consistent with the function of FBW7 and NR4A1, another FBW7 down-regulated gene in the gene expression profiling. Moreover, FBW7 potentiated cytotoxic effect of gemcitabine via activating ferroptosis and apoptosis. Combination ferroptosis inducers and apoptosis activators could also significantly potentiated cytotoxic effect of gemcitabine in pancreatic cancer. Therefore, our findings might provide new strategies for the comprehensive treatment of pancreatic cancer.
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Project description:Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths in the world. F-box/WD repeat-containing protein 7 (FBW7) plays important roles in human cancers, such as gastric cancer, breast cancer, and hepatocellular carcinoma. In this study, we found that high levels of FBW7 expression were associated with increased doxorubicin sensitivity in NSCLC cells. Down-regulation of FBW7 reduced the chemosensitivity in tumor cells. Twist is a critical transcription factor in epithelial-mesenchymal transition (EMT), and NSCLC cells with silenced Twist showed increased doxorubicin sensitivity. Treatment of cells with doxorubicin or hypoxia was shown to trigger EMT as evidenced by decreased E-cadherin and increased Vimentin. In contrast, ectopic expression of FBW7 prevented doxorubicin-or hypoxia-induced EMT. In addition, FBW7 was identified as a functional target of miR-223 in NSCLC cells. These findings define a critical role of miR-223/FBW7 pathway in regulating EMT and chemosensitivity in NSCLC cells.
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Project description:FBW7 is one of the most well characterized F-box proteins that serve as substrate recognition subunits of SCF (Skp1-Cullin 1-F-box proteins) E3 ubiquitin ligase complexes. SCFFBW7 plays key roles in regulating cell cycle progression, differentiation, and stem cell maintenance largely through targeting a broad range of oncogenic substrates for proteasome-dependent degradation. The identification of an increasing number of FBW7 substrates for ubiquitination, and intensive in vitro and in vivo studies have revealed a network of signaling components controlled by FBW7 that contributes to metabolic regulation as well as its tumor suppressor role. Here we mainly focus on recent findings that highlight a critical role for FBW7 in cancer and metabolism.
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Project description:F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between FBW7 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The impact of FBW7 on migration was further validated in vitro. Whole-genome expression microarray (GEO,accession numbers GSE76443), was then analyzed to find the possible target of FBW7. The results were verified by functional experiments in vitro and IHC staining of TMA. Finally, luciferase and chromatin immunoprecipitation (ChIP) assays were carried out to identify the possible mechanisms. The expression level of FBW7 in TMA was negatively correlated with serum CEA level, venous invasion, N stage and M stage, and positively associated with the survival of CRC patients(P<0.05). Ectopic FBW7 expression significantly suppressed migration of colon cancer cells in vitro. GEO analysis revealed that decreased FBW7 significantly correlated with increased level of CEACAM5, which encoded CEA. The correlation was verified by IHC of TMA and silencing CEACAM5 inhibited migration in vitro. Mechanistically, we demonstrated that CEACAM5 was a HIF1? target gene and that FBW7 regulated CEACAM5 in a HIF1?-dependent manner. In conclusion, our results revealed that FBW7 suppressed migration through regulation of the HIF1?/CEACAM5 axis in colorectal cancer. Therefore, our study sheds novel lights on the impact of FBW7 on HIF1?/CEACAM5 signaling axis and constitutes potential prognostic predictors and therapeutic targets for CRC.
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