Identification of GAPDH as a protein target of the saframycin antiproliferative agents.

Abstract

Saframycin A (SafA) is a member of a class of natural products with potent antiproliferative effects in leukemia- and tumor-derived cells. This activity is frequently conjectured to derive from the ability of saframycins to covalently modify duplex DNA. We used a DNA-linked affinity purification technique to identify GAPDH as a protein target of DNA-small molecule adducts of several members of the saframycin class. Nuclear translocation of GAPDH occurs upon treatment of cancer cells with saframycins, and depletion of cellular GAPDH levels by small interfering RNA transfection confers drug resistance. Roeder and coworkers have recently suggested that GAPDH is a key transcriptional coactivator necessary for entry into S phase. Our data suggest that GAPDH is also capable of forming a ternary complex with saframycin-related compounds and DNA that induces a toxic response in cells. These studies implicate a previously unknown molecular mechanism of antiproliferative activity and, given that one member of the saframycin class has shown efficacy in cancer treatment, suggest that GAPDH may be a potential target for chemotherapeutic intervention.

• Authors: Chengguo Xing, Jacob R LaPorte, Joseph K Barbay, Andrew G Myers
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 16 Pg. 5862-6 (Apr 20 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15079082 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• DNA Adducts
• DNA Primers
• Isoquinolines
• RNA, Small Interfering
• Glyceraldehyde-3-Phosphate Dehydrogenases
• saframycin A

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Base Sequence
• Blotting, Southwestern
• Cell Line
• Chromatography, Affinity
• DNA Adducts
• DNA Primers
• Glyceraldehyde-3-Phosphate Dehydrogenases (drug effects, genetics, metabolism)
• Glycolysis
• Humans
• Isoquinolines (pharmacology)
• Protein Transport
• RNA, Small Interfering (genetics)