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PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer
- Source :
- PLoS ONE, Vol 11, Iss 9, p e0163768 (2016), PLoS ONE
- Publication Year :
- 2016
- Publisher :
- Public Library of Science (PLoS), 2016.
-
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.
- Subjects :
- 0301 basic medicine
Cell cycle checkpoint
Cancer Treatment
lcsh:Medicine
Apoptosis
Biology
Research and Analysis Methods
Biochemistry
Focal adhesion
03 medical and health sciences
0302 clinical medicine
Cyclins
Gastrointestinal Tumors
Medicine and Health Sciences
medicine
Cell Cycle and Cell Division
Post-Translational Modification
Phosphorylation
lcsh:Science
Cell Cycle Inhibitors
Staining
Tumor microenvironment
Multidisciplinary
Cell Death
lcsh:R
Cancers and Neoplasms
Biology and Life Sciences
Proteins
Cell Staining
Cancer
Cell Biology
medicine.disease
Molecular biology
Blot
Gastric Cancer
030104 developmental biology
Oncology
Cell Processes
Specimen Preparation and Treatment
030220 oncology & carcinogenesis
Cancer cell
lcsh:Q
Signal transduction
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 11
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....b444e68304177299246fc408618f83b2