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The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells

Niessner, H., Beck, D., Sinnberg, T., Lasithiotakis, K., Maczey, E., Gogel, J., Venturelli, S., Berger, A., Mauthe, M., Toulany, M., Flaherty, K., Schaller, M., Schadendorf, D., Proikas-Cezanne, T., Schittek, B., Garbe, C., Kulms, D. & Meier, F., Feb-2011, In : Journal of Investigative Dermatology. 131, 2, p. 468-479 12 p.

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  • The Farnesyl Transferase Inhibitor Lonafarnib Inhibits mTOR Signaling and Enforces Sorafenib-Induced Apoptosis in Melanoma Cells

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DOI

  • Heike Niessner
  • Daniela Beck
  • Tobias Sinnberg
  • Konstantinos Lasithiotakis
  • Evelyn Maczey
  • Jeannette Gogel
  • Sascha Venturelli
  • Alexander Berger
  • Mario Mauthe
  • Mahmoud Toulany
  • Keith Flaherty
  • Martin Schaller
  • Dirk Schadendorf
  • Tassula Proikas-Cezanne
  • Birgit Schittek
  • Claus Garbe
  • Dagmar Kulms
  • Friedegund Meier

Farnesyl transferase inhibitors (FTIs) inhibit the farnesylation of proteins, including RAS and RHEB (Ras homolog enriched in brain). RAS signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways, which have a major role in melanoma progression. RHEB positively regulates mammalian target of rapamycin (mTOR). We investigated the effects of the FTI lonafarnib alone and in combination with MAPK (mitogen-activated protein kinase) or AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma) pathway inhibitors on proliferation, survival, and invasive tumor growth of melanoma cells. Lonafarnib alone did not sufficiently inhibit melanoma cell growth. Combinations of lonafarnib with AKT pathway inhibitors did not significantly increase melanoma cell growth inhibition. In contrast, combinations of lonafarnib with MAPK pathway inhibitors yielded additional growth-inhibiting effects. In particular, the combination of the FTI lonafarnib with the pan-RAF inhibitor sorafenib synergistically inhibited melanoma cell growth, significantly enhanced sorafenib-induced apoptosis, and completely suppressed invasive tumor growth in monolayer and organotypic cultures, respectively. Apoptosis induction was associated with upregulation of the endoplasmic reticulum stress-related transcription factors p8 and CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), and downregulation of the antiapoptotic Bcl-2 (B-cell lymphoma-2) family protein Mcl-1(myeloid cell leukemia 1). Lonafarnib did not affect MAPK and AKT but did affect mTOR signaling. Together, these findings suggest that the FTI lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells and may therefore represent an effective alternative for melanoma treatment.

Original languageEnglish
Pages (from-to)468-479
Number of pages12
JournalJournal of Investigative Dermatology
Volume131
Issue number2
Publication statusPublished - Feb-2011

    Keywords

  • Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Basic Helix-Loop-Helix Transcription Factors/metabolism, Benzenesulfonates/pharmacology, Cell Line, Tumor, Endoplasmic Reticulum/drug effects, Farnesyltranstransferase/antagonists & inhibitors, Humans, Melanoma/metabolism, Mitogen-Activated Protein Kinase Kinases/metabolism, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins/metabolism, Niacinamide/analogs & derivatives, Phenylurea Compounds, Piperidines/pharmacology, Proto-Oncogene Proteins c-akt/metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, Pyridines/pharmacology, Signal Transduction/drug effects, Skin Neoplasms/metabolism, Sorafenib, TOR Serine-Threonine Kinases/antagonists & inhibitors, Transcription Factor CHOP/metabolism

ID: 72812665