Cancer research (Chicago, Ill.), 2017-08, Vol.77 (16), p.4328-4341
2017
Details
- Autor(en) / Beteiligte
- Titel
- Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1-MAPK Interaction
- Ist Teil von
- Cancer research (Chicago, Ill.), 2017-08, Vol.77 (16), p.4328-4341
- Ort / Verlag
- United States: American Association for Cancer Research, Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.CAN-16-3143Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5581962
- Format
- –
- Schlagworte
- Activation, Adenocarcinoma, Antimetabolites, Antineoplastic - pharmacology, Carcinoma, Pancreatic Ductal - drug therapy, Carcinoma, Pancreatic Ductal - genetics, Cell Line, Tumor, Cell lines, Deoxycytidine - analogs & derivatives, Deoxycytidine - pharmacology, Drug Resistance, Neoplasm, Enzymatic activity, Extracellular signal-regulated kinase, Fructose, Fructose-Bisphosphatase - genetics, Fructose-Bisphosphatase - metabolism, Gemcitabine, Gluconeogenesis, GTPase-activating protein, Guanosine triphosphatases, Humans, IQGAP1 protein, MAP kinase, MAP Kinase Signaling System - drug effects, Mimicry, Pancreatic cancer, Pancreatic Neoplasms - drug therapy, Pancreatic Neoplasms - genetics, Pancreatic Neoplasms - metabolism, Phosphorylation, Raf protein, ras GTPase-Activating Proteins - antagonists & inhibitors, ras GTPase-Activating Proteins - metabolism, Signal Transduction, Transcription, Transfection, Tumor suppressor genes