The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma

Kumazoe, Motofumi; Takai, Mika; Hiroi, Shun; Takeuchi, Chieri; Kadomatsu, Mai; Nojiri, Takashi; Onda, Hiroaki; Bae, Jae‐Hoon; Huang, Yuhui; Takamatsu, Kanako; Yamashita, Shigeki; Kangawa, Kenji; Tachibana, Hirofumi

doi:10.1074/jbc.m116.772111

Cited by 36 publications

(40 citation statements)

References 35 publications

(53 reference statements)

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“…As several studies point out the potential oncogenic properties of FOXO3 in different cancer types, pharmacological inhibition of FOXO3 is of great interest for novel therapeutic interventions in these cancers [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. In accordance, we could demonstrate that nuclear FOXO3 promotes tumor angiogenesis in vivo [18] and chemoprotection in vitro [19] in aggressive NB.…”

Section: Discussionsupporting

confidence: 78%

“…Drug resistance is also mediated by the FOXO-FOXM1 axis thereby promoting tumorigenesis and cancer progression [26]. In breast cancer FOXO3 modulates tumor progression by promoting cell invasion via the induction of matrix metalloproteinases [7] and in pancreatic cancer active FOXO3 correlates with poor prognosis as it acts as an essential regulator of CD44 + stem cells [14,15]. In line, Zhou et al recently demonstrated that FOXO3 is highly expressed in pancreatic cancer tissues.…”

Section: Introductionmentioning

confidence: 97%

“…FOXO3 has been characterized as tumor suppressor gene based on its anti-proliferative and pro-apoptotic functions [2]. However, an increasing number of studies point out the "dark side" of FOXO3 and describe its potential oncogenic properties in different cancer types, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), breast cancer, glioblastoma, and pancreatic cancer [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Our own studies demonstrate that nuclear FOXO3 promotes tumor angiogenesis in vivo [18] and chemoresistance in vitro [19] in aggressive NB.…”

Section: Introductionmentioning

confidence: 99%

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A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma

et al. 2019

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The transcription factor FOXO3 has been associated in different tumor entities with hallmarks of cancer, including metastasis, tumor angiogenesis, maintenance of tumor-initiating stem cells, and drug resistance. In neuroblastoma (NB), we recently demonstrated that nuclear FOXO3 promotes tumor angiogenesis in vivo and chemoresistance in vitro. Hence, inhibiting the transcriptional activity of FOXO3 is a promising therapeutic strategy. However, as no FOXO3 inhibitor is clinically available to date, we used a medium-throughput fluorescence polarization assay (FPA) screening in a drugrepositioning approach to identify compounds that bind to the FOXO3-DNA-binding-domain (DBD). Carbenoxolone (CBX), a glycyrrhetinic acid derivative, was identified as a potential FOXO3-inhibitory compound that binds to the FOXO3-DBD with a binding affinity of 19 µM. Specific interaction of CBX with the FOXO3-DBD was validated by fluorescencebased electrophoretic mobility shift assay (FAM-EMSA). CBX inhibits the transcriptional activity of FOXO3 target genes, as determined by chromatin immunoprecipitation (ChIP), DEPP-, and BIM promoter reporter assays, and real-time RT-PCR analyses. In high-stage NB cells with functional TP53, FOXO3 triggers the expression of SESN3, which increases chemoprotection and cell survival. Importantly, FOXO3 inhibition by CBX treatment at pharmacologically relevant concentrations efficiently repressed FOXO3-mediated SESN3 expression and clonogenic survival and sensitized high-stage NB cells to chemotherapy in a 2D and 3D culture model. Thus, CBX might be a promising novel candidate for the treatment of therapy-resistant high-stage NB and other "FOXO-resistant" cancers.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma

et al. 2019

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“…PGC-1β is a member of this family and acts as a central regulator in energy metabolism and other biological processes. And it exerts an important role in different cancers: Kumazoe et al proved the FOXO3/PGC-1β signaling axis was essential for sustain the pancreatic ductal adenocarcinoma cancer stem cell properties [37]; Bellafante et al reported the overexpression of PGC-1β has the ability to provide balance between enhanced mitochondrial activity and promoted intestinal carcinogenesis [38]. However, the direct correlation and specific molecular mechanism between PGC-1β and breast cancer development remain unclear.…”

Section: Discussionmentioning

confidence: 99%

PGC-1β cooperating with FOXA2 inhibits proliferation and migration of breast cancer cells

Cao¹,

Wang²,

Wang³

et al. 2019

Cancer Cell Int

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Background: Breast cancer is one of the most common malignancy among females from the worldwide cancer incidence statistics. Peroxisome gamma coactivator-1β (PGC-1β) has long been identified to be involved in this type of tumorigenesis. However, the mechanisms of PGC-1β in human breast cancer have not been fully understood and the function requires to be further elucidated. Methods: mRNA and protein expression of PGC-1β and FOXA2 in breast cancer tissues and cell lines were determined by qRT-PCR and Western Blotting, respectively. To further visualize the expression and localization of PGC-1β and FOXA2, immunochemistry and immunofluorescence staining methods were employed. The effect of PGC-1β and FOXA2 on cell proliferation and migration were evaluated by CCK8, clone formation, transwell and wound-healing assays, which has been done either with stable PGC-1β knockdown or FOXA2 overexpression in vitro. Xenografts model of nude mice were used to evaluate tumor growth in vivo. In addition, proteins expression of the PI3K-AKT-mTOR signaling pathway involved in the regulation of breast cancer were detected by Western Blotting. Results: Our results showed that PGC-1β was upregulated and FOXA2 was downregulated in breast cancer tissues and cell lines. These two proteins can be interacted with each other to form the complex. Also, we found the combination of PGC-1β interference with FOXA2 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth in vivo. We further identified that PGC-1β and FOXA2 strongly correlated with the PI3K-AKT-mTOR signaling pathway, and they exerted their biological functions by activating this pathway. Conclusions: We demonstrated that downregulation of PGC-1β combined with overexpression of FOXA2 obviously inhibited the function of breast cancer cells through regulating the PI3K-AKT-mTOR pathway.

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“…More than 580,000 new cases of liver cancer occur in Asia every year [2]. Progressive accumulation of alterations in cancer drives genes and dysregulation of their associated signaling pathways, causing the occurrence and progression of HCC [3]. HCC is insensitive to radiotherapy and chemotherapy, and there is no uniform standard for the optimal dose of radiotherapy [4].…”

mentioning

confidence: 99%

PLK1 Is Implicated in the Poor Prognosis of Hepatocellular Carcinoma

Xun¹,

Lu²,

Wang³

2020

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We aimed to identify if PLK1 could be used as a new diagnostic and therapeutic biomarker in hepatocellular carcinoma (HCC) patient. Expression of PLK1 in HCC was analyzed by using GEPIA (Gene Expression Profiling Interactive Analysis) and UALCAN databases. GEPIA and CBioPortal tools were applied to determine patients' survival and PLK1 mutations, respectively. PPI (Protein-Protein Interaction) networks were further built by STRING (Search Tool for the Retrieval of Interacting Genes) and Metascape Web portals. The data demonstrated that the expression of PLK1 in HCC was significantly enhanced when compared to normal liver tissues (P < 0.001). A higher PLK1 expression resulted in a remarkably shorter disease-free survival as well as overall survival. Moreover, the expression of PLK1 in HCC was related to HCC patients' grade and race, but not gender. The data also suggested that expression of PLK1 elevated gradually from stage 1 to 3 but decreased in stage 4. Three specific gene mutations K146R, S335Afs*120 and D429H of PLK1 occurred in HCC and these unique mutations were not seen in any other tumor tissues. Finally, PPI networks and GO enrichment analysis suggested that PLK1 might be associated with cell cycle and p53 signaling pathway etc. Taken together, our novel findings suggest that PLK1 is implicated in the poor prognosis of hepatocellular carcinoma.

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The FOXO3/PGC-1β signaling axis is essential for cancer stem cell properties of pancreatic ductal adenocarcinoma

Cited by 36 publications

References 35 publications

A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma

A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma

PGC-1β cooperating with FOXA2 inhibits proliferation and migration of breast cancer cells

PLK1 Is Implicated in the Poor Prognosis of Hepatocellular Carcinoma

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