Abstract | BACKGROUND: 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: 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.
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Authors | Edgar Selzer, Christiane Thallinger, Christoph Hoeller, Philipp Oberkleiner, Volker Wacheck, Hubert Pehamberger, Burkhard Jansen |
Journal | Molecular medicine (Cambridge, Mass.)
(Mol Med)
Vol. 8
Issue 12
Pg. 877-84
(Dec 2002)
ISSN: 1076-1551 [Print] England |
PMID | 12606824
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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