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Chemical Targeting of GAPDH Moonlighting Function in Cancer Cells Reveals Its Role in Tubulin Regulation
- Source :
- Chemistry & Biology. 21(11):1533-1545
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- Summary Glycolytic enzymes are attractive anticancer targets. They also carry out numerous, nonglycolytic "moonlighting" functions in cells. In this study, we investigated the anticancer activity of the triazine small molecule, GAPDS, that targets the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDS showed greater toxicity against cancer cells compared to a known GAPDH enzyme inhibitor. GAPDS also selectively inhibited cell migration and invasion. Our analysis showed that GAPDS treatment reduced GAPDH levels in the cytoplasm, which would modulate the secondary, moonlighting functions of this enzyme. We then used GAPDS as a probe to demonstrate that a moonlighting function of GAPDH is tubulin regulation, which may explain its anti-invasive properties. We also observed that GAPDS has potent anticancer activity in vivo. Our study indicates that strategies to target the secondary functions of anticancer candidates may yield potent therapeutics and useful chemical probes.
- Subjects :
- Cytoplasm
Cell Survival
Alpha-enolase
Clinical Biochemistry
Down-Regulation
Antineoplastic Agents
Biochemistry
stomatognathic system
Cell Movement
Tubulin
Cell Line, Tumor
Neoplasms
Drug Discovery
Animals
Humans
RNA, Messenger
Enzyme Inhibitors
Molecular Biology
Zebrafish
Glyceraldehyde 3-phosphate dehydrogenase
chemistry.chemical_classification
Pharmacology
biology
Triazines
Drug discovery
Glyceraldehyde-3-Phosphate Dehydrogenases
Cell migration
General Medicine
HCT116 Cells
Cell biology
Actin Cytoskeleton
Enzyme
chemistry
Enzyme inhibitor
Larva
Cancer cell
biology.protein
Molecular Medicine
HT29 Cells
Subjects
Details
- ISSN :
- 10745521
- Volume :
- 21
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Chemistry & Biology
- Accession number :
- edsair.doi.dedup.....bad2721b0978ddcdfa9a219a5065d58b
- Full Text :
- https://doi.org/10.1016/j.chembiol.2014.08.017