Document Detail

PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death.
MedLine Citation:
PMID:  22441669     Owner:  NLM     Status:  MEDLINE    
To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor-specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death.
E-M Schweikert; A Devarajan; I Witte; P Wilgenbus; J Amort; U Förstermann; A Shabazian; V Grijalva; D M Shih; R Farias-Eisner; J F Teiber; S T Reddy; S Horke
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-23
Journal Detail:
Title:  Cell death and differentiation     Volume:  19     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-13     Completed Date:  2013-06-19     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  1549-60     Citation Subset:  IM    
Department of Pharmacology, University Medical Center of the Johannes-Gutenberg University Mainz, Obere Zahlbacher Str. 67, 55131 Mainz, Germany.
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MeSH Terms
Aryldialkylphosphatase / biosynthesis*,  genetics
Cytochromes c / genetics,  metabolism
Endoplasmic Reticulum / genetics,  metabolism,  pathology
Gene Expression Regulation, Enzymologic*
Gene Expression Regulation, Neoplastic*
HEK293 Cells
MAP Kinase Signaling System*
Mitochondria / enzymology,  genetics
Neoplasm Proteins / biosynthesis*,  genetics
Neoplasms / enzymology*,  genetics,  pathology
Superoxides / metabolism*
Up-Regulation / genetics
Grant Support
Reg. No./Substance:
0/Neoplasm Proteins; 11062-77-4/Superoxides; 9007-43-6/Cytochromes c; EC; EC protein, human; EC protein, mouse

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