ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer

Ji, Shunrong; Qin, Yi; Shi, Si; Lei, Yu; Hu, Hongli; Zhou, Hu; Gao, Jing; Zhang, Bo; Xu, Wenyan; Liu, Jiang; Liang, Dingkong; Liu, Liang; Liu, Chen; Jiang, Long; Zhou, Haijun; Chiao, Paul J.; Xu, Jin; Ni, Quanxing; Gao, Daming; Yu, Xianjun

doi:10.1038/cr.2015.30

Cited by 118 publications

(127 citation statements)

References 47 publications

(64 reference statements)

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“…Among these substrates, HIF1a, PGC1a, and c-Myc are well-known regulators of metabolism. We previously reported that the expression of c-Myc decreased dramatically when FBW7 was overexpressed in pancreatic cancer (8). However, no change in the expression of PGC1a or HIF1a was observed upon FBW7 upregulation in pancreatic cancer.…”

Section: Txnip Is a Negative Regulator Of Glucose Metabolismmentioning

confidence: 99%

“…Emerging evidence has shown that FBW7 is also regulated by multiple upstream genes, such as p53, Pin1, Hes-5, and Numb4, as well as by miRNAs (7). We previously reported that fewer than 2% of pancreatic cancer samples harbored FBW7 mutations, according to sequencing analysis (8). Furthermore, with mass spectrometry analysis, we detected that ERK kinase phosphorylated FBW7 at the T205 site, which resulted in destabilization of FBW7 in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

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FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

Qin

Liang

et al. 2016

Clinical Cancer Research

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Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.Experimental Design: Combining maximum standardized uptake value (SUV max ), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUV max and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways. Results:The expression level of FBW7 was negatively associated with SUV max in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ( 18 F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a cMyc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner.Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer.

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Section: Txnip Is a Negative Regulator Of Glucose Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

Qin

Liang

et al. 2016

Clinical Cancer Research

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“…Immunohistochemical staining of paraffin-embedded tissues with antibodies for MUC16, phosphorylation of ERK (p-ERK), c-Myc, and FBW7 were performed and scored to determine the proteins expression according to standard procedures described previously (23).…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

Liang

Qin

Zhang

et al. 2017

Molecular Cancer Research

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“…For example, 1 study has reported that a p53‐FBW7‐Aurora B axis, which identified FBW7 as a transcriptional target of p53 21. Another study found that FBW7 could be phosphorylated and destabilized by ERK kinase 25. More intriguingly, just before this work was finished, Yang's team discovered a novel circ‐FBW7 in glioma cells, which is able to antagonize the inhibitory effect of USP28 on FBW7α so as to degrade c‐Myc 26.…”

Section: Discussionmentioning

confidence: 99%

FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

Lin¹,

Qiu

et al. 2018

Cancer Science

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F‐box and WD repeat domain‐containing 7 (FBW7) is a SCF‐type E3 ubiquitin ligase targeting a multitude of oncoproteins for degradation. Acting as one of the most important tumor suppressors, it is frequently inactivated in various tumors. In this study we aimed to evaluate the relationship of FBW7 with glioma pathology and prognosis, and examine its effect in glioma malignancies and temozolomide (TMZ)‐based therapy. Clinical tissues and TCGA database analysis revealed that FBW7 expression was correlated inversely with glioma histology and positively with patient survival time. Lentivirus transfection‐induced FBW7 overexpression significantly suppressed proliferation, invasion and migration of U251 and U373 cells, whereas knockdown of FBW7 by targeted shRNA promoted proliferation, invasion and migration of glioma cells. Most importantly, the expression level of FBW7 was found to affect the 50% inhibitory concentration (IC50) of U251 and the TMZ‐resistant variant. Combining TMZ with FBW7 overexpression notably increased the cytotoxicity compared to TMZ treatment alone, which was conversely attenuated by FBW7 knockdown. Moreover, flow cytometry (FC) analysis showed overexpression of FBW7, TMZ or the combination‐increased proportion of G2/M arrest and the apoptotic rate, whereas FBW7 inhibition reduced G2/M arrest and apoptosis in U251 cells. Finally, mechanistic study found that FBW7 overexpression downregulated Aurora B, Mcl1 and Notch1 levels in a time‐dependent pattern and this expressional suppression was independent of TMZ. These findings collectively demonstrate the critical role of FBW7 as a prognostic factor and a potential target to overcome chemoresistance of glioblastoma.

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ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer

Cited by 118 publications

References 47 publications

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

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