Cotargeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cells by necrosis independently of RIPK1 and RIPK3 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-06-06

AUTHORS

F Lai, S T Guo, L Jin, C C Jiang, C Y Wang, A Croft, M N Chi, H-Y Tseng, M Farrelly, B Atmadibrata, J Norman, T Liu, P Hersey, X D Zhang

ABSTRACT

Past studies have shown that histone deacetylase (HDAC) and mutant BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors synergistically kill melanoma cells with activating mutations in BRAF. However, the mechanism(s) involved remains less understood. Here, we report that combinations of HDAC and BRAF inhibitors kill BRAFV600E melanoma cells by induction of necrosis. Cotreatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) or panobinostat (LBH589) and the BRAF inhibitor PLX4720 activated the caspase cascade, but caspases appeared dispensable for killing, in that inhibition of caspases did not invariably block induction of cell death. The majority of dying cells acquired propidium iodide positivity instantly when they became positive for Annexin V, suggesting induction of necrosis. This was supported by caspase-independent release of high-mobility group protein B1, and further consolidated by rupture of the plasma membrane and loss of nuclear and cytoplasmic contents, as manifested by transmission electron microscopic analysis. Of note, neither the necrosis inhibitor necrostatin-1 nor the small interference RNA (siRNA) knockdown of receptor-interacting protein kinase 3 (RIPK3) inhibited cell death, suggesting that RIPK1 and RIPK3 do not contribute to induction of necrosis by combinations of HDAC and BRAF inhibitors in BRAFV600E melanoma cells. Significantly, SAHA and the clinically available BRAF inhibitor vemurafenib cooperatively inhibited BRAFV600E melanoma xenograft growth in a mouse model even when caspase-3 was inhibited. Taken together, these results indicate that cotreatment with HDAC and BRAF inhibitors can bypass canonical cell death pathways to kill melanoma cells, which may be of therapeutic advantage in the treatment of melanoma. More... »

PAGES

e655-e655

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/cddis.2013.192

    DOI

    http://dx.doi.org/10.1038/cddis.2013.192

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1038550518

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/23744355


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