title: Prenylation inhibition-induced cell death in melanoma: reduced sensitivity in BRAF mutant/PTEN wild-type melanoma cells.
abstract: While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells.
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary; National Koranyi Institute of TB and Pulmonology, Budapest, Hungary; Department of Biological Physics, Eötvös University, Budapest, Hungary.
authors: Tamás
authors: T
authors: Garay
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: István
authors: I
authors: Kenessey
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Eszter
authors: E
authors: Molnár
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Éva
authors: É
authors: Juhász
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Andrea
authors: A
authors: Réti
authors: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors: Viktória
authors: V
authors: László
authors: National Koranyi Institute of TB and Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors: Anita
authors: A
authors: Rózsás
authors: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors: Judit
authors: J
authors: Dobos
authors: National Koranyi Institute of TB and Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; Department of Thoracic Surgery, Semmelweis University-National Institute of Oncology, Budapest, Hungary.
authors: Balázs
authors: B
authors: Döme
authors: Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Walter
authors: W
authors: Berger
authors: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors: Walter
authors: W
authors: Klepetko
authors: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors: József
authors: J
authors: Tóvári
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary; MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
authors: József
authors: J
authors: Tímár
authors: Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Balázs
authors: B
authors: Hegedűs
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004164:Diphosphonates / Q000627:therapeutic use*; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D054876:Prenylation / Q000187:drug effects*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D008565:Membrane Proteins; D000077211:Zoledronic Acid; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
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