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Betulinic acid-induced Mcl-1 expression in human melanoma--mode of action and functional significance.

AbstractBACKGROUND:
Currently there is no information on the regulation of expression and physiological role of the anti-apoptotic protein Mcl-1 in cells of the melanocytic lineage. This study investigates the regulation and expression of Mcl-1 in human melanoma cells, which was recently found to be induced by betulinic acid, a compound with anti-melanoma and apoptosis-inducing potential.
MATERIALS AND METHODS:
Mcl-1 phosphorthioate antisense oligonucleotides were used to investigate the effect of downregulating the expression of Mcl-1. Regulation of Mcl-1 expression was analyzed with the specific PI3-kinase inhibitors LY294002 and wortmannin and the inhibitor of MAP-kinase activation, PD98059. Western blot analysis was performed with anti ERK1/2, Mcl-1, Bak, Bcl-x and Bax antibodies. Activation status of PI-3 kinase and MAP-kinase pathways was investigated using phospho-Akt and phosphorylation-state independent Akt as well as phospho-MAP kinase, phospho-MEK and phospho-GSK-3alpha/beta antibodies.
RESULTS:
Upregulation of Mcl-1 in human melanoma cells by betulinic acid is mediated via a signal-transduction pathway that is inhibited by LY294002 and wortmannin. Betulinic acid-induced phosphorylation and activation of the Akt protein kinase was inhibited by LY294002. The inhibitor PD98059 reduced expression levels of Mcl-1 in melanoma cells and this effect was counteracted by betulinic acid. Downregulation of Mcl-1 by antisense oligodeoxynucleotides in combination with betulinic treatment led to a synergistic effect regarding growth inhibition.
CONCLUSIONS:
These results suggest that in human melanoma cells Mcl-1 is (i) of functional relevance for survival and (ii) subject to dual regulation by the MAP- kinase pathway and a pathway involving protein kinase B/Akt, the latter of which is modulated in response to betulinic acid. This study provides an experimental foundation for future therapeutic strategies using anti-Mcl-1 antisense oligonucleotides in human melanoma.
AuthorsEdgar Selzer, Christiane Thallinger, Christoph Hoeller, Philipp Oberkleiner, Volker Wacheck, Hubert Pehamberger, Burkhard Jansen
JournalMolecular medicine (Cambridge, Mass.) (Mol Med) Vol. 8 Issue 12 Pg. 877-84 (Dec 2002) ISSN: 1076-1551 [Print] England
PMID12606824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Pentacyclic Triterpenes
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Triterpenes
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin
  • Betulinic Acid
Topics
  • Androstadienes (pharmacology)
  • Cell Culture Techniques
  • Chromones (pharmacology)
  • Enzyme Inhibitors (pharmacology)
  • Humans
  • Melanoma (metabolism)
  • Morpholines (pharmacology)
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins (biosynthesis, genetics)
  • Pentacyclic Triterpenes
  • Phosphorylation
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins (metabolism)
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Triterpenes (metabolism)
  • Wortmannin
  • Betulinic Acid

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