Fructose-1,6-bisphosphatase inhibits ERK activation and bypasses gemcitabine resistance in pancreatic cancer by blocking IQGAP1–MAPK interaction

Xin Jin, Yunqian Pan, Liguo Wang, Tao Ma, Lizhi Zhang, Amy H. Tang, Daniel D Billadeau, Heshui Wu, Haojie Huang

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4328-4341
Number of pages14
JournalCancer Research
Volume77
Issue number16
DOIs
StatePublished - Aug 15 2017

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gemcitabine
Fructose-Bisphosphatase
Pancreatic Neoplasms
Adenocarcinoma
Gluconeogenesis
Mitogen-Activated Protein Kinase Kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fructose-1,6-bisphosphatase inhibits ERK activation and bypasses gemcitabine resistance in pancreatic cancer by blocking IQGAP1–MAPK interaction. / Jin, Xin; Pan, Yunqian; Wang, Liguo; Ma, Tao; Zhang, Lizhi; Tang, Amy H.; Billadeau, Daniel D; Wu, Heshui; Huang, Haojie.

In: Cancer Research, Vol. 77, No. 16, 15.08.2017, p. 4328-4341.

Research output: Contribution to journalArticle

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AU - Zhang, Lizhi

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