<scp>AKT</scp>‐phosphorylated <scp>FOXO</scp>1 suppresses <scp>ERK</scp> activation and chemoresistance by disrupting <scp>IQGAP</scp>1‐<scp>MAPK</scp> interaction

Pan, Chuyue; Jin, Xin; Zhao, Yuxi; Pan, Yunqian; Yang, Jing; Karnes, R. Jeffrey; Zhang, Jun; Wang, Liguo; Huang, Haojie

doi:10.15252/embj.201695534

Cited by 103 publications

(70 citation statements)

References 56 publications

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“…Given that FOXO1 does not directly binds to the DNA binding motif of ERG, the exact mechanism by which FOXO1 interaction reduces ERG recruitment to its downstream targets is unclear. However, our data cannot rule out the possibility that FOXO1 interaction with the N-terminal half of ERG may affect ERG DNA binding by causing overall conformation changes in ERG protein as demonstrated in IQGAP1, another FOXO1 interacting protein (27). …”

Section: Resultsmentioning

confidence: 63%

“…PTEN loss leads to AKT and CDK1- or CDK2-mediated phosphorylation of FOXO1, exclusion of FOXO1 from the nucleus, and loss of the tumor suppressor functions in the nucleus (15,22–24). Increasing evidence suggests that AKT-phosphorylated FOXO1 also possesses tumor suppressor functions in the cytoplasm (25–27). In agreement with these findings, proteosome degradation of AKT-phosphorylated FOXO1 is critical for PI3K-AKT-mediated cell transformation and oncogenesis (28–30).…”

Section: Introductionmentioning

confidence: 99%

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Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion

et al. 2017

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E26 transformation-specific (ETS) transcription factor ERG is aberrantly overexpressed in approximately 50% of all human PCa due to TMPRSS2-ERG gene rearrangements. However, mice with prostate-specific transgenic expression of PCa-associated ERG alone fail to develop PCa, highlighting that ERG requires other lesions to drive prostate tumorigenesis. Forkhead box (FOXO) transcription factor FOXO1 is a tumor suppressor that is frequently inactivated in human PCa. Here we demonstrate that FOXO1, but not other FOXO proteins (FOXO3 and FOXO4), binds and inhibits the transcriptional activity of PCa-associated ERG independently of FOXO1 transcriptional activity. Knockdown of endogenous FOXO1 increased invasion of TMPRSS2-ERG fusion positive VCaP cells, an effect completely abolished by ERG knockdown. Patient specimen analysis demonstrated that FOXO1 and ERG protein expression inversely correlated in a subset of human PCa. Although human ERG transgene expression or homozygous deletion of Foxo1 alone in the mouse prostate failed to promote tumorigenesis, concomitant ERG transgene expression and Foxo1 deletion resulted in upregulation of ERG target genes, increased cell proliferation and formation of high-grade prostatic intraepithelial neoplasia (HGPIN). Overall, we provide biochemical and genetic evidence that aberrantly activated ERG cooperates with FOXO1 deficiency to promote prostate tumorigenesis and cell invasion. Our findings enhance understanding of PCa etiology and suggest that the FOXO1-ERG signaling axis can be a potential target for treatment of PCa.

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Section: Resultsmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion

et al. 2017

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“…2A; refs. 6–8, 18, 19). Similar to these findings, we demonstrated that IQGAP1 interacted with components of the MAPK pathway in PANC-1 cells (Fig.…”

Section: Resultsmentioning

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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“…Drug resistance is identified as a major obstacle in tumor chemotherapy, and miRNAs have been reported to serve critical roles in this process (17)(18)(19)(20)(21)(22)(23). To date, several studies have identified that miR-149 exerts a critical function in numerous types of tumors.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-149 suppresses the proliferation and increases the sensitivity of ovarian cancer cells to cisplatin by targeting X-linked inhibitor of apoptosis

et al. 2018

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Abstract. Currently, ovarian cancer is identified as one of the leading causes of cancer-associated mortality in females. Despite numerous efforts that were made on developing novel treatments for ovarian cancer, the survival rate remains unsatisfactory. Considering the important regulatory role of miRNAs in different types of cancer, the present study aims to identify a novel therapeutic target for treatment of ovarian cancer. The expression of miR-149 was detected using reverse transcription-quantitative polymerase chain reaction in cancerous and normal cells. Furthermore, the effects of miR-149 on ovarian cancer cell activities were investigated using MTT assay, colony formation, flow cytometry and western blotting analysis. In the present study, it was revealed that microRNA (miR)-149 was significantly downregulated in ovarian cancer tissues and cell lines, and that the miR-149 expression was correlated with the patient prognosis. In addition, it was observed that forced expression of miR-149 increased the sensitivity of ovarian cancer cell to cisplatin. Based on bioinformatics analysis and luciferase assay, X-linked inhibitor of apoptosis (XIAP) was identified as a direct target gene of miR-149 in ovarian cancer cells. It was also demonstrated that XIAP expression was upregulated in the ovarian cancer tissues and cell lines, while it was negatively correlated with miR-149 in these tissues and cells. Furthermore, results revealed that ectopic expression of XIAP was able to abolish the miR-149-enhanced cell sensitivity to cisplatin. In conclusion, the present study revealed that miR-149 functioned as a tumor suppressor in the progression of ovarian cancer, increasing the sensitivity of ovarian cancer cells to cisplatin treatment.

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AKT‐phosphorylated FOXO1 suppresses ERK activation and chemoresistance by disrupting IQGAP1‐MAPK interaction

Cited by 103 publications

References 56 publications

Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion

Loss of FOXO1 Cooperates with TMPRSS2–ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion

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

MicroRNA-149 suppresses the proliferation and increases the sensitivity of ovarian cancer cells to cisplatin by targeting X-linked inhibitor of apoptosis

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