Borst, Andreas and Haferkamp, Sebastian and Grimm, Johannes and Roesch, Manuel and Zhu, Guannan and Guo, Sen and Li, Chunying and Gao, Tianwen and Meierjohann, Svenja and 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. ISSN 0304-3835, 1872-7980
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled 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 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:20 |
| Last Modified: | 14 Feb 2019 10:05 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2158 |
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