TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma
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TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma. / Menon, Dinoop R; Wels, Christian; Bonyadi Rad, Ehsan; Joshi, Shripad; Knausz, Heike; Lade-Keller, Johanne; Brandner, Johanna M; Schaider, Helmut.
in: PIGM CELL MELANOMA R, Jahrgang 26, Nr. 6, 01.11.2013, S. 912-6.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma
AU - Menon, Dinoop R
AU - Wels, Christian
AU - Bonyadi Rad, Ehsan
AU - Joshi, Shripad
AU - Knausz, Heike
AU - Lade-Keller, Johanne
AU - Brandner, Johanna M
AU - Schaider, Helmut
N1 - © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Caspase 3
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Humans
KW - Indoles
KW - Melanoma
KW - Mitogen-Activated Protein Kinase Kinases
KW - Nuclear Proteins
KW - Proto-Oncogene Proteins B-raf
KW - Pyridones
KW - Pyrimidinones
KW - Sulfonamides
KW - Transforming Growth Factor beta1
KW - Tumor Necrosis Factor-alpha
KW - Twist Transcription Factor
U2 - 10.1111/pcmr.12139
DO - 10.1111/pcmr.12139
M3 - SCORING: Journal article
C2 - 23848983
VL - 26
SP - 912
EP - 916
JO - PIGM CELL MELANOMA R
JF - PIGM CELL MELANOMA R
SN - 1755-1471
IS - 6
ER -
