title: Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigenetic integrator UHRF1.
abstract: METHODS
  Curcumin inhibits proliferation of many cancer cells. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) and/or cyclic guanosine-3',5'-monophosphate (cGMP), play a pivotal role in signalling pathways involved in cell proliferation. Therefore, this study investigated PDE1-5 participations in the anti-proliferative properties of curcumin in B16F10 murine melanoma cells.
  
  
  RESULTS
  We report that curcumin inhibits PDE1-5 activities (IC(50) ≅10(-5)  M), indicating that curcumin acts as a non-selective PDE inhibitor. In melanoma cells, PDE4 and PDE1 represent the major cAMP-PDEs and cGMP-PDEs activities, respectively. Curcumin treatment decreased PDE1 and PDE4 activities and dose dependently increased intracellular cGMP levels, whereas cAMP levels were unchanged. Curcumin inhibited cell proliferation and cell cycle progression by accumulating cells in the S- and G2/M-phases with enhanced expressions of cyclin-dependent kinase inhibitors. In contrast, expressions of PDE1A, cyclin A and the epigenetic integrator ubiquitin-like containing PHD and Ring Finger domains 1 (UHRF1) and DNA methyltransferase 1 (DNMT1) were decreased by curcumin. Interestingly, PDE1A overexpression increased UHRF1 and DNMT1 expressions and rescued the B16F10 cells from curcumin anti-proliferative effects. Nimodipine, a PDE1 inhibitor, mimicked the curcumin effects.
  
  
  CONCLUSIONS
  Curcumin exerts its anti-cancer property by targeting PDE1 that inhibits melanoma cell proliferation via UHRF1, DNMT1, cyclin A, p21 and p27 regulations. This suggests that natural PDE1 inhibitors present in food might be effective in preventing cancer.
authors: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors: Abdurazzag
authors: A
authors: Abusnina
authors: Thérèse
authors: T
authors: Keravis
authors: Issaka
authors: I
authors: Yougbaré
authors: Christian
authors: C
authors: Bronner
authors: Claire
authors: C
authors: Lugnier
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D022762:CCAAT-Enhancer-Binding Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C527988:Pde1A protein, mouse; D006152:Cyclic GMP; D003474:Curcumin