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PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer

View Article: PubMed Central - PubMed

ABSTRACT

PFKFB3 (6-phosphofructo-2-kinase) synthesizes fructose 2,6-bisphosphate (F2,6P2), which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. Overexpression of the PFKFB3 enzyme leads to high glycolytic metabolism, which is required for cancer cells to survive in the harsh tumor microenvironment. The objective of this study was to investigate the antitumor activity of PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), a small molecule inhibitor of PFKFB3, against gastric cancer and to explore its potential mechanisms. The effects of PFK15 on proliferation, apoptosis and cell cycle progression in gastric cancer cells were evaluated by cytotoxicity and apoptosis assays, flow cytometry, and western blotting. In addition, the invasion inhibition effects of PFK15 were measured by transwell invasion assay and western blot analysis, and a xenograft tumor model was used to verify the therapeutic effect of PFK15 in vivo. Results showed that PFK15 inhibited the proliferation, caused cell cycle arrest in G0/G1 phase by blocking the Cyclin-CDKs/Rb/E2F signaling pathway, and induced apoptosis through mitochondria in gastric cancer cells. Tumor volume and weight were also significantly reduced upon intraperitoneal injection with PFK15 at 25 mg/kg. In addition, PFK15 inhibited the invasion of gastric cancer cells by downregulating focal adhesion kinase (FAK) expression and upregulating E-cadherin expression. Taken together, our findings indicate that PFK15 is a promising anticancer drug for treating gastric cancer.

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Related in: MedlinePlus

Mechanism of PFK15-induced cell cycle arrest in G0/G1 phase.Cells were treated with various concentration of PFK15 for 24 h. The cell cycle associated proteins were checked by western bolt assay. PFK15 treatment significantly decreased expressions of cyclin D1, cyclin E1, phosphorylated Rb and the nuclear transfactor E2F-1 levels while increased non-phosphorylated Rb protein levels in both MKN45 and AGS cell lines.
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pone.0163768.g003: Mechanism of PFK15-induced cell cycle arrest in G0/G1 phase.Cells were treated with various concentration of PFK15 for 24 h. The cell cycle associated proteins were checked by western bolt assay. PFK15 treatment significantly decreased expressions of cyclin D1, cyclin E1, phosphorylated Rb and the nuclear transfactor E2F-1 levels while increased non-phosphorylated Rb protein levels in both MKN45 and AGS cell lines.

Mentions: To examine the molecular mechanism responsible for the induced cell cycle block in G0/G1 phase by PFK15, the expression levels of G0/G1 regulatory proteins were determined. We observed that the expression levels of cyclin D1 and cyclin E1 were remarkably reduced by PFK15 after 24 h treatment at concentrations of 7 and 9 μmol/L in both cell lines (Fig 3). However, the compound had no effect on the protein levels of CDK 2, CDK 4 and CDK 6.


PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer
Mechanism of PFK15-induced cell cycle arrest in G0/G1 phase.Cells were treated with various concentration of PFK15 for 24 h. The cell cycle associated proteins were checked by western bolt assay. PFK15 treatment significantly decreased expressions of cyclin D1, cyclin E1, phosphorylated Rb and the nuclear transfactor E2F-1 levels while increased non-phosphorylated Rb protein levels in both MKN45 and AGS cell lines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036843&req=5

pone.0163768.g003: Mechanism of PFK15-induced cell cycle arrest in G0/G1 phase.Cells were treated with various concentration of PFK15 for 24 h. The cell cycle associated proteins were checked by western bolt assay. PFK15 treatment significantly decreased expressions of cyclin D1, cyclin E1, phosphorylated Rb and the nuclear transfactor E2F-1 levels while increased non-phosphorylated Rb protein levels in both MKN45 and AGS cell lines.
Mentions: To examine the molecular mechanism responsible for the induced cell cycle block in G0/G1 phase by PFK15, the expression levels of G0/G1 regulatory proteins were determined. We observed that the expression levels of cyclin D1 and cyclin E1 were remarkably reduced by PFK15 after 24 h treatment at concentrations of 7 and 9 μmol/L in both cell lines (Fig 3). However, the compound had no effect on the protein levels of CDK 2, CDK 4 and CDK 6.

View Article: PubMed Central - PubMed

ABSTRACT

PFKFB3 (6-phosphofructo-2-kinase) synthesizes fructose 2,6-bisphosphate (F2,6P2), which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. Overexpression of the PFKFB3 enzyme leads to high glycolytic metabolism, which is required for cancer cells to survive in the harsh tumor microenvironment. The objective of this study was to investigate the antitumor activity of PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), a small molecule inhibitor of PFKFB3, against gastric cancer and to explore its potential mechanisms. The effects of PFK15 on proliferation, apoptosis and cell cycle progression in gastric cancer cells were evaluated by cytotoxicity and apoptosis assays, flow cytometry, and western blotting. In addition, the invasion inhibition effects of PFK15 were measured by transwell invasion assay and western blot analysis, and a xenograft tumor model was used to verify the therapeutic effect of PFK15 in vivo. Results showed that PFK15 inhibited the proliferation, caused cell cycle arrest in G0/G1 phase by blocking the Cyclin-CDKs/Rb/E2F signaling pathway, and induced apoptosis through mitochondria in gastric cancer cells. Tumor volume and weight were also significantly reduced upon intraperitoneal injection with PFK15 at 25 mg/kg. In addition, PFK15 inhibited the invasion of gastric cancer cells by downregulating focal adhesion kinase (FAK) expression and upregulating E-cadherin expression. Taken together, our findings indicate that PFK15 is a promising anticancer drug for treating gastric cancer.

No MeSH data available.


Related in: MedlinePlus