Asymmetric dimethylarginine attenuates serum starvation-induced apoptosis via suppression of the Fas (APO-1/CD95)/JNK (SAPK) pathway

Cell Death Dis. 2013 Oct 3;4(10):e830. doi: 10.1038/cddis.2013.345.

Abstract

Asymmetric dimethylarginine (ADMA) is synthesized by protein arginine methyltransferases during methylation of protein arginine residues and released into blood upon proteolysis. Higher concentrations of ADMA in blood have been observed in patients with metabolic diseases and certain cancers. However, the role of ADMA in colon cancer has not been well investigated. ADMA serum levels in human patients diagnosed with colon cancer were found to be higher than those present in healthy subjects. ADMA treatment of LoVo cells, a human colon adenocarcinoma cell line, attenuated serum starvation-induced apoptosis and suppressed the activation of the Fas (APO-1/CD95)/JNK (SAPK) (c-Jun N terminal protein kinase/stress-activated protein kinase)pathway. ADMA also suppressed the activation of JNK triggered by death receptor ligand anti-Fas mAb and exogenous C2-ceramide. Moreover, we demonstrated that ADMA pretreatment protected LoVo cells from doxorubicin hydrochloride-induced cell death and activation of the Fas/JNK pathway. In summary, our results suggest that the elevated ADMA in colon cancer patients may contribute to the blocking of apoptosis of cancer cells in response to stress and chemotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects*
  • Arginine / analogs & derivatives*
  • Arginine / blood
  • Arginine / pharmacology
  • Case-Control Studies
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Colonic Neoplasms / blood
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / pathology
  • Culture Media, Serum-Free / pharmacology
  • Doxorubicin / pharmacology
  • Enzyme Activation / drug effects
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Male
  • Middle Aged
  • Signal Transduction / drug effects*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • fas Receptor / metabolism*

Substances

  • Antibodies, Monoclonal
  • Culture Media, Serum-Free
  • FAS protein, human
  • N-acetylsphingosine
  • fas Receptor
  • N,N-dimethylarginine
  • Doxorubicin
  • Arginine
  • JNK Mitogen-Activated Protein Kinases
  • Sphingosine