Glucose-Dependent FOXM1 Promotes Epithelial-to-Mesenchymal Transition Via Cellular Metabolism and Targeting Snail in Human Pancreatic Cancer

Kyuno, Takuro; Kohno, Takayuki; Konno, Takumi; Yamaguchi, Hiroshi; Kyuno, Daisuke; Imamura, Masafumi; Kimura, Yasutoshi; Kojima, Takashi; Takemasa, Ichiro

doi:10.1097/mpa.0000000000001485

Cited by 10 publications

(7 citation statements)

References 26 publications

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“…On the contrary, PANC‐1 spheroids showed a lower invasive behavior: higher growth in area is evident, but individual cells did not leave spheroid in none of examined conditions. Probably, this is due to a limited chemotactic stimulus and a low concentration of glucose, 65 that was used as chemoattractant. In fact, it is known that high glucose concentration, after about 48 h, is expected to induce epithelial‐mesenchymal transition (EMT) in epithelial cell lines, by which cells lose epithelial cell–cell adhesion with improved tendency to move through extracellular matrix 66 .…”

Section: Summary and Discussionmentioning

confidence: 99%

Diffusion‐induced anisotropic cancer invasion: A novel experimental method based on tumor spheroids

et al. 2022

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Tumour invasion is strongly influenced by microenvironment and, among other parameters, chemical stimuli play an important role. An innovative methodology for the quantitative investigation of chemotaxis in vitro by live imaging of morphology of cell spheroids, in 3D collagen gel, is presented here. The assay was performed by using a chemotactic chamber to impose a controlled gradients of nutrients (glucose) on spheroids, mimicking the chemotactic stimuli naturally occurring in the proximity of blood vessels. Different tumoral cell lines (PANC-1 and HT-1080) are compared to non-tumoral ones (NIH/3T3). Morphology response is observed by means a Time-lapse workstation equipped with an incubating system and quantified by image analysis techniques. Description of invasion phenomena was based on an engineering approach, based on transport phenomena concepts. As expected, NIH/3T3 spheroids are characterized by a limited tendency of cells to invade the surrounding tissue, unlike PANC-1 and HT-1080 that show relatively stronger response to gradients.

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Section: Summary and Discussionmentioning

confidence: 99%

Diffusion‐induced anisotropic cancer invasion: A novel experimental method based on tumor spheroids

et al. 2022

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“…For example, a proteomics study of the breast cancer cell line MCF-7 revealed that FOXM1 altered the expression of 37 proteins associated with mitochondrial biogenesis and glycolysis [ 294 ]. In pancreatic cancer, FOXM1 expression was upregulated in a glucose-dependent manner, which correlated with epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cell lines [ 310 ]. In addition, downregulation of FOXM1 induced pancreatic cancer cells to use mitochondrial respiration rather than aerobic glycolysis in high-glucose medium, further linking FOXM1 to the glycolytic pathway [ 310 ].…”

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

“…In pancreatic cancer, FOXM1 expression was upregulated in a glucose-dependent manner, which correlated with epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cell lines [ 310 ]. In addition, downregulation of FOXM1 induced pancreatic cancer cells to use mitochondrial respiration rather than aerobic glycolysis in high-glucose medium, further linking FOXM1 to the glycolytic pathway [ 310 ]. Similarly, FOXM1 knockdown decreased glucose utilization, lactate production, and lactate dehydrogenase (LDH) activity in several pancreatic cell lines and downregulated phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA) [ 311 ].…”

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.

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“…Compared with small molecule PROTACs, the design and synthesis of p-PROTACs is simpler, and possess the ability to target “undruggable” targets with high specificity and low toxicity, and can resist to mutation targets. Since GLUT1 levels can correlate with response to FOXM1, there is increasing interest in understanding cell proliferation and glycolysis [ 42 , 43 ]. However, while PD-L1 regulation has been extensively studied in cancer cells, the specific link between PD-L1 and FOXM1 has received less attention.…”

Section: Discussionmentioning

confidence: 99%

Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression

Wang

Dai

Yu³

et al. 2022

J Exp Clin Cancer Res

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Background Peptide proteolysis-targeting chimeras (p-PROTACs) with advantages of high specificity and low toxicity have emerged as a powerful technology of targeted protein degradation for biomedical applications. FOXM1, a proliferation-associated transcription factor, is overexpressed in a variety of human tumors as a key driver of tumorigenesis and cancer progression, and is a potential anticancer therapeutic target. However, FOXM1-targeting p-PROTACs has not been researched. Methods Here, we first analyzed the expression of FOXM1, GLUT1 and PD-L1 in liver cancer through database and clinical samples of patients. FOXM1-targeting peptides, selected by screening phage display library, are verified its targeting effect by immunofluorescence and CCK-8 test. The novel p-PROTAC degrader of FOXM1 is chemically synthesis, named FOXM1-PROTAC, by linking a FOXM1-binding antagonistic peptide, with the E3 ubiquitin ligase recruitment ligand Pomalidomide and with the cell membrane penetrating peptide TAT. Its degradation effect on FOXM1 was detected by Western blotting, qPCR, and we verified its effect on the behavior of cancer cells by flow cytometry, scratch assay, and Transwell in vitro. The tumor xenografted mice model was used for evaluating FOXM1-PROTAC therapeutic response in vivo. Finally, we detected the expression of GLUT1 and PD-L1 after FOXM1-PROTAC degraded FOXM1 by using Western Blotting and hippocampal detectors and dual immunofluorescence. Results We found that the novel FOXM1-PROTAC efficiently entered cells and induced degradation of FOXM1 protein, which strongly inhibits viability as well as migration and invasion in various cancer cell lines, and suppressed tumor growth in HepG2 and MDA-MB-231 cells xenograft mouse models, without detected toxicity in normal tissues. Meanwhile, FOXM1-PROTAC decreased the cancer cells glucose metabolism via downregulating the protein expression levels of glucose transporter GLUT1 and the immune checkpoint PD-L1, which suggests involvement of FOXM1 in cancer cell metabolism and immune regulation. Conclusions Our results indicate that biologically targeted degradation of FOXM1 is an attractive therapeutic strategy, and antagonist peptide-containing FOXM1-PROTACs as both degrader and inhibitor of FOXM1 could be developed as a safe and promising drug for FOXM1-overexpressed cancer therapy.

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Glucose-Dependent FOXM1 Promotes Epithelial-to-Mesenchymal Transition Via Cellular Metabolism and Targeting Snail in Human Pancreatic Cancer

Cited by 10 publications

References 26 publications

Diffusion‐induced anisotropic cancer invasion: A novel experimental method based on tumor spheroids

Diffusion‐induced anisotropic cancer invasion: A novel experimental method based on tumor spheroids

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression

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