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

Garay, Tamás and Kenessey, István and Molnár, Eszter and Juhász, Éva and Réti, Andrea and Laszlo, Viktoria and Rózsás, Anita and Dobos, Judit and Döme, Balázs and Berger, Walter and Klepetko, Walter and Tóvári, József and Tímár, József and Hegedűs, Balázs (2015) Prenylation inhibition-induced cell death in melanoma: reduced sensitivity in BRAF mutant/PTEN wild-type melanoma cells. PLOS ONE, 10 (2). e0117021. ISSN 1932-6203

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Abstract

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeu- tic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the respons e 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 measure- ments, 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 de monstrated no significant synergism in cell vi- ability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro . Importantly, zole- dronic 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 apo- ptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. A ltogether our data demons trates 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.

Item Type: Article
Subjects: R Medicine / orvostudomány > RL Dermatology / bőrgyógyászat
Depositing User: Elvira Rigóné Kálé
Date Deposited: 29 Jul 2015 13:57
Last Modified: 29 Jul 2015 13:57
URI: http://real.mtak.hu/id/eprint/25676

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