NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells

Zhu, Yi; Shi, Minmin; Chen, Hao; Gu, Jiangning; Zhang, Jiaqiang; Shen, Baiyong; Deng, Xiaxing; Xie, Junjie; Zhan, Xi; Peng, Chenghong

doi:10.18632/oncotarget.4167

Cited by 62 publications

(61 citation statements)

References 24 publications

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“…Decreased expression of FBP1 associates with advanced tumor stage and poor overall survival in PDAC patients (11). Ectopic expression of FBP1 inhibits tumor growth in renal carcinoma and hepatocellular carcinoma (10, 12).…”

Section: Discussionmentioning

confidence: 99%

Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction

et al. 2017

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Dysregulation of the MAPK pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase-activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and ERK. Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here, we demonstrate that FBP1 acts as a negative modulator of the IQGAP1–MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity. Conversely, decreased FBP1 expression induced pERK1/2 levels in PDAC cell lines and correlated with increased pERK1/2 levels in patient specimens. Treatment with gemcitabine caused undesirable activation of ERK1/2 in PDAC cells, but cotreatment with the FBP1-derived small peptide inhibitor FBP1 E4 overcame gemcitabine-induced ERK activation, thereby increasing the anticancer efficacy of gemcitabine in PDAC. These findings identify a primary mechanism of resistance of PDAC to standard therapy and suggest that the FBP1–IQGAP1–ERK1/2 signaling axis can be targeted for effective treatment of PDAC.

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Section: Discussionmentioning

confidence: 99%

Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction

et al. 2017

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“…NPM1 is over-expressed in a variety of solid tumours of different histological origin including prostate [47], liver [48], thyroid [49], colon [50], gastric [51], pancreas [52], glioma and glioblastoma [53, 54], astrocytoma [55] and others. NPM1 overexpression often correlates with mitotic index and metastatization and it has been proposed as an adverse prognostic marker in a number of such malignancies [5, 56].…”

Section: Npm1 and Cancermentioning

confidence: 99%

Molecules that target nucleophosmin for cancer treatment: an update

et al. 2016

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Nucleophosmin is a highly and ubiquitously expressed protein, mainly localized in nucleoli but able to shuttle between nucleus and cytoplasm. Nucleophosmin plays crucial roles in ribosome maturation and export, centrosome duplication, cell cycle progression, histone assembly and response to a variety of stress stimuli. Much interest in this protein has arisen in the past ten years, since the discovery of heterozygous mutations in the terminal exon of the NPM1 gene, which are the most frequent genetic alteration in acute myeloid leukemia. Nucleophosmin is also frequently overexpressed in solid tumours and, in many cases, its overexpression correlates with mitotic index and metastatization. Therefore it is considered as a promising target for the treatment of both haematologic and solid malignancies. NPM1 targeting molecules may suppress different functions of the protein, interfere with its subcellular localization, with its oligomerization properties or drive its degradation. In the recent years, several such molecules have been described and here we review what is currently known about them, their interaction with nucleophosmin and the mechanistic basis of their toxicity. Collectively, these molecules exemplify a number of different strategies that can be adopted to target nucleophosmin and we summarize them at the end of the review.

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“…Therefore, low FBP1 expression allows HIF to increase PDK1, LDHA, GLUT1 and VEGF mRNA levels, turning glycolytic flux toward anaerobic metabolism and promoting cancer. The mechanisms that lead to FBP1 under-expression in RCC are not yet elucidated, however in pancreatic cancer cells nucleophosmin (NPM1) was shown to repress FBP1 by binding directly to the promoter at the E-box motif [46]. In primary gastric carcinoma NF-kappaB seems to silence FBP1 through hypermethylation of the promoter [47].…”

Section: Energy Sensing Pathwaysmentioning

confidence: 99%