Inactivation of protein tyrosine phosphatases by oltipraz and other cancer chemopreventive 1,2-dithiole-3-thiones.
Dithiolethiones upregulate the expression of cancer-preventive proteins via modification of thiol residues in the Keap1-Nrf2 transcription factor complex. In addition to Keap1-Nrf2, dithiolethiones have the potential to modify a variety of cysteine-containing proteins in the cell. Such 'off target' reactions could contribute to either side effects or cancer-preventive efficacy. Evidence is presented here that cancer chemopreventive dithiolethiones inactivate protein tyrosine phosphatases via covalent, but thiol-labile, modification of active site residues. This observation may explain a number of previously reported cellular responses to dithiolethiones.
Bhattacharyya
Sanjib
S
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA.
Zhou
Haiying
H
Seiner
Derrick R
DR
Gates
Kent S
KS
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D006801:Humans; D013058:Mass Spectrometry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D011719:Pyrazines; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C049325:1,2-dithiol-3-thione