title: TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma.
abstract: 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.
authors.affiliation: Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria; Center for Medical Research, Medical University of Graz, Graz, Austria.
authors.forename: Dinoop R
authors.initials: DR
authors.lastname: Menon
authors.forename: Christian
authors.initials: C
authors.lastname: Wels
authors.forename: Ehsan
authors.initials: E
authors.lastname: Bonyadi Rad
authors.forename: Shripad
authors.initials: S
authors.lastname: Joshi
authors.forename: Heike
authors.initials: H
authors.lastname: Knausz
authors.forename: Johanne
authors.initials: J
authors.lastname: Lade-Keller
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Brandner
authors.forename: Helmut
authors.initials: H
authors.lastname: Schaider
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D009687:Nuclear Proteins; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; C103173:TWIST1 protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051879:Twist-Related Protein 1; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D053148:Caspase 3
keywords: BRAF; TGF-β1; TNF-α; Twist1; drug resistance