title: Chemical targeting of GAPDH moonlighting function in cancer cells reveals its role in tubulin regulation.
abstract: 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.
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 500-712, Republic of Korea.
authors.forename: Da-Woon
authors.initials: DW
authors.lastname: Jung
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 500-712, Republic of Korea.
authors.forename: Woong-Hee
authors.initials: WH
authors.lastname: Kim
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 500-712, Republic of Korea.
authors.forename: Shinae
authors.initials: S
authors.lastname: Seo
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 500-712, Republic of Korea.
authors.forename: Eunsang
authors.initials: E
authors.lastname: Oh
authors.affiliation: College of Public Health and Welfare, Dongshin University, 185 Geonjaero, Naju, Jeonnam 520-714, Republic of Korea.
authors.forename: Soon-Ho
authors.initials: SH
authors.lastname: Yim
authors.affiliation: College of Pharmacy, Sunchon National University, Sunchon 570-742, Republic of Korea.
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Ha
authors.affiliation: Department of Chemistry and MedChem Program of Life Sciences Institute, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore; Laboratory of Bioimaging Probe Development, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138667, Singapore.
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.affiliation: New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-Dong, Buk-Gu, Gwangju 500-712, Republic of Korea. Electronic address: darren@gist.ac.kr.
authors.forename: Darren Reece
authors.initials: DR
authors.lastname: Williams
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*; D015027:Zebrafish / Q000254:growth & development
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014227:Triazines; D014404:Tubulin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases