Identification of GAPDH as a protein target of the saframycin antiproliferative agents.
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.
Xing
Chengguo
C
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02128, USA.
LaPorte
Jacob R
JR
Barbay
Joseph K
JK
Myers
Andrew G
AG
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D026501:Blotting, Southwestern; D002460:Cell Line; D002846:Chromatography, Affinity; D018736:DNA Adducts; D017931:DNA Primers; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D018736:DNA Adducts; D017931:DNA Primers; D007546:Isoquinolines; D034741:RNA, Small Interfering; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C026925:saframycin A