Prenylation inhibition-induced cell death in melanoma: Reduced sensitivity in BRAF mutant/PTEN wild-type melanoma cells

Tamás Garay, István Kenessey, Eszter Molnár, Éva Juhász, Andrea Réti, Viktória László, Anita Rózsás, Judit Dobos, Balázs Döme, Walter Berger, Walter Klepetko, József Tóvári, József Tímár, Balázs Hegedus

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Abstract

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAFmutant 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 PTENmutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration ofmelanoma 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 mousemodels were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth ofmelanoma cells in vivo. Zoledronic acidmore efficiently decreased short-term in vitro viability in NRASmutant cells when compared to BRAFmutant 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 BRAFmutant but PTEN wild-typemelanoma 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 NRASmutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivitymight 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.

Original languageEnglish
Article numbere0117021
JournalPloS one
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 3 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Garay, T., Kenessey, I., Molnár, E., Juhász, É., Réti, A., László, V., Rózsás, A., Dobos, J., Döme, B., Berger, W., Klepetko, W., Tóvári, J., Tímár, J., & Hegedus, B. (2015). Prenylation inhibition-induced cell death in melanoma: Reduced sensitivity in BRAF mutant/PTEN wild-type melanoma cells. PloS one, 10(2), [e0117021]. https://doi.org/10.1371/journal.pone.0117021