The Farnesyl Transferase Inhibitor Lonafarnib Inhibits mTOR Signaling and Enforces Sorafenib-Induced Apoptosis in Melanoma Cells Heike Niessner, Daniela.

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The Farnesyl Transferase Inhibitor Lonafarnib Inhibits mTOR Signaling and Enforces Sorafenib-Induced Apoptosis in Melanoma Cells 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 Journal of Investigative Dermatology Volume 131, Issue 2, Pages 468-479 (January 2011) DOI: 10.1038/jid.2010.297 Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Lonafarnib inhibits farnesylation of the farnesyl transferase target HDJ2. Melanoma cells (BLM, MV3, MEWO, and SKMel19) were incubated with increasing concentrations of lonafarnib (0.1, 1, and 5μM) for 24hours, followed by western blotting with anti-HDJ2 to detect the farnesylated (faster migrating band) and unfarnesylated (slower migrating band) forms of this farnesyl transferase target. Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Lonafarnib and sorafenib synergistically inhibit melanoma cell growth. Growth assay (4-methylumbelliferyl heptanoate (MUH)) of melanoma cell lines (BLM, MV3, MEWO, and SKMel19) (a) and of melanoma cells directly isolated from excised skin metastases (b) treated with lonafarnib (lona) or/and sorafenib (sora) for 72hours. The percentage of growth inhibition compared with DMSO-treated controls is shown on the y axis (*P<0.05). (c) Real-time proliferation assay of melanoma cells (BLM) treated with DMSO as control (ctrl), lonafarnib or/and sorafenib, rapamycin (rapa) or/and sorafenib, and Triton X-100 0.1% as positive control for cell death. (d) Response surface analysis of melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with lonafarnib and sorafenib for 72hours (+ superadditive effects). (e) Growth assay (MUH) of melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with increasing concentrations of PLX4032. Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Lonafarnib potentiates sorafenib-induced apoptosis of melanoma cells. (a) Cell cycle distribution of melanoma cells (BLM, MV3, MEWO, and SKMel19) and (b) human fibroblasts 48hours after treatment with DMSO as control, lonafarnib, or/and sorafenib. (c) Electron microscopy of melanoma cells (BLM) treated with DMSO as control and lonafarnib (lona) plus sorafenib (sora) for 24hours. In the control cells, cell membrane, mitochondria, and nucleus are intact (arrows). Treated cells are packed into membrane vesicles (arrows). Scale bar=2μm. (d) Western blot analysis of melanoma cells (BLM, MV3, MEWO, and SKMel19) 24hours after treatment with lonafarnib or/and sorafenib for B-cell lymphoma-2 (Bcl-2), Bcl-extra large (Bcl-xL), and myeloid cell leukemia 1 (Mcl-1). Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Lonafarnib potentiates sorafenib-induced apoptosis of melanoma cells. (a) Cell cycle distribution of melanoma cells (BLM, MV3, MEWO, and SKMel19) and (b) human fibroblasts 48hours after treatment with DMSO as control, lonafarnib, or/and sorafenib. (c) Electron microscopy of melanoma cells (BLM) treated with DMSO as control and lonafarnib (lona) plus sorafenib (sora) for 24hours. In the control cells, cell membrane, mitochondria, and nucleus are intact (arrows). Treated cells are packed into membrane vesicles (arrows). Scale bar=2μm. (d) Western blot analysis of melanoma cells (BLM, MV3, MEWO, and SKMel19) 24hours after treatment with lonafarnib or/and sorafenib for B-cell lymphoma-2 (Bcl-2), Bcl-extra large (Bcl-xL), and myeloid cell leukemia 1 (Mcl-1). Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Lonafarnib combined with sorafenib abrogates invasive tumor growth of melanoma cells in organotypic skin culture. BLM melanoma cells were seeded onto organotypic skin cultures and were treated with DMSO as control (ctrl), lonafarnib (lona), or/and sorafenib (sora). Organotypic skin cultures were stained with (a) hematoxylin and eosin (HE) or (b) the proliferation marker Ki67. BLM melanoma cells or Ki67-positive cells in organotypic skin cultures were counted. Mean±SD of direct counting of six high-powered fields are depicted. Scale bar=10μm. Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Lonafarnib does not inhibit MAPK (mitogen-activated protein kinase) and AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma) signaling but does inhibit mTOR (mammalian target of rapamycin) signaling. (a) Western blot analysis of melanoma cells (BLM, MV3, MEWO, and SKMel19) 24hours after treatment with lonafarnib (lona) or sorafenib (sora) for total and phosphorylated extracellular signal-regulated kinase (ERK) and AKT. (b) RAS activity in melanoma cells (BLM, MV3, MEWO, and SKMel19) following treatment with lonafarnib for 24hours was analyzed using a RAS activation assay. Guanosine triphosphate (GTP)-bound active p21 RAS was isolated from lysates by affinity precipitation with a GST-RBD fusion protein followed by immunoblot analysis with pan-RAS antibody. The fusion protein (42kDa) was detected by Ponceau S red staining. (c) Western blot analysis of melanoma cells 24hours after treatment with lonafarnib for phosphorylated p70 S6 kinase (p-p70S6K) and S6 ribosomal protein (p-S6P). Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Lonafarnib augments sorafenib-induced upregulation of p8 and CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein). (a) Relative expression of p8 in melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with DMSO as control (ctrl), lonafarnib (lona), or/and sorafenib (sora) for 12hours using quantitative real-time PCR. (b) Western blot analysis of melanoma cells (BLM, MV3, MEWO, and SKMel19) 24hours after treatment with lonafarnib or/and sorafenib for CHOP. (c) Growth assay (4-methylumbelliferyl heptanoate (MUH)) of melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with increasing concentrations of thapsigargin for 72hours. Cell cycle distribution of melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with DMSO as control and thapsigargin for 48hours. Relative expression of p8 in melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with DMSO as control and thapsigargin for 12hours using quantitative real-time PCR. Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Lonafarnib augments sorafenib-induced upregulation of p8 and CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein). (a) Relative expression of p8 in melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with DMSO as control (ctrl), lonafarnib (lona), or/and sorafenib (sora) for 12hours using quantitative real-time PCR. (b) Western blot analysis of melanoma cells (BLM, MV3, MEWO, and SKMel19) 24hours after treatment with lonafarnib or/and sorafenib for CHOP. (c) Growth assay (4-methylumbelliferyl heptanoate (MUH)) of melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with increasing concentrations of thapsigargin for 72hours. Cell cycle distribution of melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with DMSO as control and thapsigargin for 48hours. Relative expression of p8 in melanoma cells (BLM, MV3, MEWO, and SKMel19) treated with DMSO as control and thapsigargin for 12hours using quantitative real-time PCR. Journal of Investigative Dermatology 2011 131, 468-479DOI: (10.1038/jid.2010.297) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions