TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma

Autor:	Johanna M. Brandner, Heike Knausz, Johanne Lade-Keller, Shripad Joshi, Helmut Schaider, Christian Wels, Ehsan Bonyadi Rad, Dinoop Ravindran Menon
Rok vydání:	2013
Předmět:	Proto-Oncogene Proteins B-raf Programmed cell death Indoles animal structures Pyridones Apoptosis Pyrimidinones Dermatology General Biochemistry Genetics and Molecular Biology Transforming Growth Factor beta1 Cell Line Tumor medicine Humans Gene silencing Melanoma Transcription factor TGF beta 1 Mitogen-Activated Protein Kinase Kinases Sulfonamides biology Caspase 3 Tumor Necrosis Factor-alpha MEK inhibitor Twist-Related Protein 1 Nuclear Proteins medicine.disease Vemurafenib Oncology Drug Resistance Neoplasm biology.protein Cancer research Tumor necrosis factor alpha Transforming growth factor
Zdroj:	Menon, D R, Wels, C, Bonyadi Rad, E, Joshi, S, Knausz, H, Lade-Keller, J, Brandner, J M & Schaider, H 2013, ' TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma ', Pigment Cell & Melanoma Research, vol. 26, no. 6, pp. 912-6 . https://doi.org/10.1111/pcmr.12139
ISSN:	1755-1471
DOI:	10.1111/pcmr.12139
Popis:	Summary: Resistance to BRAF and MEK inhibition is a common phenomenon in melanoma. Cytokines and transcription factors have been attributed to contribute to the loss of sensitivity towards these inhibitors. Here, we show that transforming growth factor (TGF)-β1 if combined with PLX4032, a BRAF inhibitor, or GSK1120212, a MEK inhibitor, substantially increased cell death in BRAF-mutant melanoma cell lines. This increase was based on the combined regulatory decrease in Twist1, an antiapoptotic protein. Overexpression or silencing of Twist1 attenuated or aggravated induction of apoptosis through PLX4032 or GSK1120212, respectively. Exposure to tumour necrosis factor (TNF)-α, however, led to increased Twist1 levels and oppositional decrease in cell death if exposed to PLX4032 or GSK1120212. This increase in drug resistance again depended on Twist1 levels. Our studies suggest that Twist1 as a common downstream target of multiple signalling cascades plays a crucial role in mediating drug resistance to BRAF- and MEK-targeted molecular inhibitors.
Databáze:	OpenAIRE
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