BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells

Elisa Sala, Luca Mologni, Silvia Truffa, Carlo Gaetano, Gideon E. Bollag, Carlo Gambacorti-Passerini

Research output: Contribution to journalArticlepeer-review

Abstract

BRAF-activating mutations have been reported in several types of cancer, including melanoma (∼70% of cases), thyroid (30-70%), ovarian (15-30%), and colorectal cancer (5-20%). Mutant BRAF has constitutive kinase activity and causes hyperactivation of the mitogen-activated protein kinase pathway. BRAF silencing induces regression of melanoma xenografts, indicating the essential role of BRAF for cell survival. We set up an inducible short hairpin RNA system to compare the role of oncogenic BRAF in thyroid carcinoma versus melanoma cells. Although BRAF knockdown led to apoptosis in the melanoma cell line A375, the anaplastic thyroid carcinoma cell ARO underwent growth arrest upon silencing, with little or no cell death. Reexpression of the thyroid differentiation marker, sodium iodide symporter, was induced after long-term silencing. The different outcome of BRAF down-regulation in the two cell lines was associated with an opposite regulation of p21CIP1/WAF1 expression levels in response to the block of the BRAF mitogenic signal. These results were confirmed using a specific BRAF small-molecule inhibitor, PLX4032. Restoration of p21CIP1/WAF1 expression rescued melanoma cells from death. Altogether, our data indicate that oncogenic BRAF inhibition can have a different effect on cell fate depending on the cellular type. Furthermore, we suggest that a BRAF-independent mechanism of cell survival exists in anaplastic thyroid cancer cells.

Original languageEnglish
Pages (from-to)751-759
Number of pages9
JournalMolecular Cancer Research
Volume6
Issue number5
DOIs
Publication statusPublished - May 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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