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TGF ‐β1 and TNF ‐α differentially regulate T wist1 mediated resistance towards BRAF / MEK inhibition in melanoma
Author(s) -
Me Dinoop R.,
Wels Christian,
Bonyadi Rad Ehsan,
Joshi Shripad,
Knausz Heike,
LadeKeller Johanne,
Brandner Johanna M.,
Schaider Helmut
Publication year - 2013
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12139
Subject(s) - melanoma , cancer research , apoptosis , gene silencing , tumor necrosis factor alpha , transcription factor , mapk/erk pathway , mek inhibitor , transforming growth factor , chemistry , biology , signal transduction , immunology , microbiology and biotechnology , genetics , gene
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 PLX 4032, a BRAF inhibitor, or GSK 1120212, a MEK inhibitor, substantially increased cell death in BRAF ‐mutant melanoma cell lines. This increase was based on the combined regulatory decrease in T wist1, an antiapoptotic protein. Overexpression or silencing of T wist1 attenuated or aggravated induction of apoptosis through PLX 4032 or GSK 1120212, respectively. Exposure to tumour necrosis factor ( TNF )‐α, however, led to increased T wist1 levels and oppositional decrease in cell death if exposed to PLX 4032 or GSK 1120212. This increase in drug resistance again depended on T wist1 levels. Our studies suggest that T wist1 as a common downstream target of multiple signalling cascades plays a crucial role in mediating drug resistance to BRAF ‐ and MEK ‐targeted molecular inhibitors.