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Production of Cyr61 protein is modulated by extracellular acidification and PI3K/Akt signaling in prostate carcinoma PC-3 cells.

Abstract
High expression of Cyr61, an extracellular cysteine-rich heparin-binding protein, has been associated with a malignant cell phenotype and poor outcome in prostate cancers. Although Cyr61 was found by us to be overproduced in androgen-independent PC-3 cells treated with N-acetylcysteine (NAC), its significance is still unclear. We therefore aimed to determine how and why Cyr61 protein is overexpressed in NAC-treated cells. Here, we found that Cyr61 protein level markedly increased in cells treated with NAC at high cell seeding density. Silencing of Cyr61 by siRNA induced enhanced activity of caspase-3/7, upregulation of the proapototic Bok, BimL and BimS, cleavage of apoptosis hallmarkers such as Bax, PARP and caspase-3, and downregulation of antiapoptotic Bcl2, Bcl-xL and Mcl-1 proteins. NAC treatment caused a reduction of extracellular medium pH to acidic and an increase in Akt phosphorylation, after which the replacement with NAC-free medium returned them to control levels within 24h. Acid stimulation increased the levels of Cyr61 and p-Akt proteins, whereas it suppressed the induction of proapoptotic and antiapoptotic proteins. Overall, our data indicate that PC-3 cells overproduce Cyr61 protein via activation of the PI3K/Akt signaling as a part of the survival mechanisms under the conditions causing extracellular acidity and further cytotoxicity.
AuthorsYoon-Jin Lee, David M Lee, Sang-Han Lee
JournalFood and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 58 Pg. 169-76 (Aug 2013) ISSN: 1873-6351 [Electronic] England
PMID23623839 (Publication Type: Journal Article)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Acids
  • CCN1 protein, human
  • Cysteine-Rich Protein 61
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Acetylcysteine
Topics
  • Acetylcysteine (pharmacology)
  • Acids (metabolism)
  • Apoptosis
  • Cell Line, Tumor
  • Cysteine-Rich Protein 61 (biosynthesis, genetics)
  • Gene Silencing
  • Humans
  • Male
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Prostatic Neoplasms (metabolism, pathology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Signal Transduction
  • Up-Regulation

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