Borst, Andreas, Haferkamp, Sebastian, Grimm, Johannes, Rösch, Manuel, Zhu, Guannan, Guo, Sen, Li, Chunying, Gao, Tianwen, Meierjohann, Svenja, Schrama, David and Houben, Roland
(2017)
BIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines.
Cancer Letters 404, pp. 70-78.
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Other URL: http://doi.org/10.1016/j.canlet.2017.07.005
Abstract
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E) -inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the ...
Abstract
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E) -inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells). Screening for differentially expressed apoptosis-related genes revealed loss of BCL2-Interacting Killer (BIK) mRNA in CCA-cells. Importantly, ectopic expression of BIK in CCA-cells resulted in increased apoptosis rates following vemurafenib/trametinib treatment, while knockdown/knockout of BIK in A-cells attenuated the apoptotic response. Furthermore, we demonstrate reversible epigenetic silencing of BIK mRNA expression in CCA-cells. Importantly, HDAC inhibitor treatment associated with re-expression of BIK augmented sensitivity of CCA-cells towards vemurafenib/trametinib treatment both in vitro and in vivo. In conclusion, our results suggest that BIK can be a critical mediator of melanoma cell fate determination in response to MAPK pathway inhibition. (C) 2017 Elsevier B.V. All rights reserved.
Export bibliographical data
| Item type: | Article |
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| Date: | 2017 |
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| Institutions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
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| Identification Number: | | Value | Type |
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| 10.1016/j.canlet.2017.07.005 | DOI |
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| Keywords: | BREAST-CANCER CELLS; HISTONE DEACETYLASE INHIBITORS; ENDOPLASMIC-RETICULUM BIK; POTENT ANTITUMOR-ACTIVITY; BCL-2 FAMILY-MEMBERS; PHASE-II TRIAL; BH3-ONLY PROTEIN; METASTATIC MELANOMA; MULTIPLE-MYELOMA; MEK INHIBITION; Melanoma; Vemurafenib; Trametinib; BIK/NBK; Apoptosis |
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| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine |
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| Status: | Published |
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| Refereed: | Yes, this version has been refereed |
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| Created at the University of Regensburg: | Yes |
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| Item ID: | 39768 |
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