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

Abstract

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.

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

“…Mounting evidence has pointed out c-Myc to be a Kras target (41). Moreover, we also reported that in pancreatic cancer, Kras mutation activated ERK, leading to destabilization of tumor suppressor FBW7, which ultimately led to c-Myc upregulation (24). These observations prompted us to consider MUC16 as a c-Myc downstream transcriptional target.…”

“…iKras cell lines, which express Kras G12D upon doxycycline (doxy) treatment, and human pancreatic nonmalignant epithelial HPNE cells were generously provided by Professor Paul J. Chiao. PANC-1 and SW1990 cell lines with FBW7 overexpression were generated previously (24).…”

PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells

“…Total RNA was extracted with TRIzol reagent (Invitrogen), purified using the PureLink RNA Minikit (Life Technologies), and assessed for quality and quantity using absorption measurements. The expression of candidate genes and b-actin was determined by quantitative real-time PCR, according to the standard procedures described previously (9). RNA was used for analysis of Human Oxidative Stress using pathway-focused RT-PCR array systems (The Human Oxidative Stress RT 2 Profiler PCR Array; PAHS-065ZA; Qiagen).…”

“…Accumulated evidence has demonstrated that metabolic reprogramming is an emerging hallmark of cancer (8). Our previous findings indicated that ERK kinase modulates F-box and WD repeat domain-containing 7 (FBW7) ubiquitination in a T205 phosphorylation-dependent manner, and FBW7 is a negative regulator of mitochondrial respiration in pancreatic cancer cells, thereby revealing an important function of Kras/ERK/FBW7 axis in promoting PDAC progression (7,9). However, the mechanism underlying the impact of ERK/FBW7 on mitochondrial metabolism remains unclear.…”

Mechanisms underlying18F-fluorodeoxyglucose accumulation in colorectal cancer

“…In CRC, it was recently reported that FBW7 targets CDX2 (caudal-related homeobox transcription factor 2) for degradation via two cdc42-phosphoclegron motifs in a GSK3beta-dependent manner[52]. Ji et al[53] have recently reported that KRAS mutations inhibit the tumor suppressor FBW7, which negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin binding protein) axis in pancreatic cancer. The expression level of FBW7 was negatively associated with PET/CT SUVmax in 60 pancreatic cancer patients, indicating that FBW7 is an important KRAS downstream effector and might reverse KRAS-driven metabolic change.…”