TGF-[beta]1 and TNF-[alpha] differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma

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)-[beta]1 if combined with PLX4032, a BRAF i...

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Bibliographic Details
Published in:Pigment cell and melanoma research 2013-11, Vol.26 (6), p.912
Main Authors: Menon, Dinoop R, Wels, Christian, Bonyadi Rad, Ehsan, Joshi, Shripad, Knausz, Heike, Lade-Keller, Johanne, Brandner, Johanna M, Schaider, Helmut
Format: Article
Language:English
Subjects:
Apoptosis
Drug resistance
Medical research
Melanoma
Online Access:Get full text
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Summary: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)-[beta]1 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)-[alpha], 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. [PUBLICATION ABSTRACT]
ISSN:1755-1471
1755-148X
DOI:10.1111/pcmr.12139