Antiproliferative Effect of Rottlerin on Sk-Mel-28 Melanoma CellsReportar como inadecuado




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Evidence-Based Complementary and Alternative Medicine - Volume 2015 2015, Article ID 545838, 9 pages -

Research Article

Department of Life Sciences, University of Siena, Via Aldo Moro 7, 53100 Siena, Italy

Department of Biology and Evolution, University of Ferrara, Via Luigi Borsari 46, 44100 Ferrara, Italy

Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 7, 53100 Siena, Italy

Received 2 April 2015; Accepted 17 May 2015

Academic Editor: Olumayokun A. Olajide

Copyright © 2015 Elena Daveri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Melanoma is the most aggressive and chemoresistant form of skin cancer. Mutated, constitutively active B-RAF is believed to play a crucial role, although the selective B-RAF inhibition has shown poor clinical success, since phenomena of resistance usually occur, likely arising from additional genetic aberrations, such as loss of function of p53 and PTEN, overexpression of cyclin D1, hyperactivation of NF-κB, and downregulation of p21-Cip1. Since all of them are present in the Sk-Mel-28 melanoma cells, this cell line could be an ideal, albeit hard to study, model to develop new therapeutic strategies. In the current study, we tested the cytostatic action of Rottlerin on Sk-Mel-28 melanoma cells, on the basis of the known Rottlerin effects on the main proliferative signaling pathways. We presented evidence that the drug inhibits cell growth by an Akt- and p21-Cip1-independent mechanism, involving the dual inhibition of ERK and NF-κB and downregulation of cyclin D1. In addition, we found that Rottlerin increases ERK phosphorylation, but, surprisingly, this resulted in decreased ERK activity. Pull-down experiments, using Rottlerin-CNBr-conjugated Sepharose beads, revealed that Rottlerin binds to ERK, independently from its phosphorylation status. This direct interaction could in part explain the paradoxical blockage of ERK downstream signaling and growth arrest.

We would like to dedicate this paper to the memory of our friend and colleague, prematurely deceased, Claudia Torricelli, who actively contributed to this project





Autor: Elena Daveri, Giuseppe Valacchi, Roberta Romagnoli, Emilia Maellaro, and Emanuela Maioli

Fuente: https://www.hindawi.com/



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