Mcl‐1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells

dc.contributor.authorSarif, Zina
dc.contributor.authorTolksdorf, Beatrice
dc.contributor.authorFechner, Henry
dc.contributor.authorEberle, Jürgen
dc.date.accessioned2020-12-16T09:00:34Z
dc.date.available2020-12-16T09:00:34Z
dc.date.issued2020-09-04
dc.date.updated2020-12-07T10:44:20Z
dc.description.abstractTNF‐related apoptosis‐inducing ligand (TRAIL) induces apoptosis selectively in cancer cells. For melanoma, the targeting of TRAIL signaling appears highly attractive, due to pronounced TRAIL receptor expression in tumor tissue. However, mechanisms of TRAIL resistance observed in melanoma cells may limit its clinical use. The Bcl‐2 family members are critical regulators of cell‐intrinsic apoptotic pathways. Thus, the antiapoptotic Bcl‐2 protein myeloid cell leukemia 1 (Mcl‐1) is overexpressed in many tumor types and was linked to chemotherapy resistance in melanoma. In this study, we evaluated the involvement of antiapoptotic Bcl‐2 proteins (Bcl‐2, Bcl‐xL, Bcl‐w, Mcl‐1, Bcl‐A1, and Bcl‐B) in TRAIL resistance. They were targeted by small interfering RNA‐mediated silencing in TRAIL‐sensitive (A‐375, Mel‐HO) and in TRAIL‐resistant melanoma cell lines (Mel‐2a, MeWo). This highlighted Mcl‐1 as the most efficient target to overcome TRAIL resistance. In this context, we investigated the effects of Mcl‐1‐targeting microRNAs as well as the Mcl‐1‐selective inhibitor S63845. Both miR‐193b and S63845 resulted in significant enhancement of TRAIL‐induced apoptosis, associated with decreased cell viability. Apoptosis induction was mediated by caspase‐3 processing as well as by Bax and Bak activation, indicating the critical involvement of intrinsic apoptosis pathways. These data may indicate a high relevance of Mcl‐1 targeting also in melanoma therapy. Furthermore, the data may suggest to consider the use of the tumor suppressor miR‐193b as a strategy for countering TRAIL resistance in melanoma.en
dc.identifier.eissn1098-2744
dc.identifier.issn0899-1987
dc.identifier.urihttps://depositonce.tu-berlin.de/handle/11303/12189
dc.identifier.urihttp://dx.doi.org/10.14279/depositonce-11064
dc.language.isoenen
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subject.ddc610 Medizin und Gesundheitde
dc.subject.otherMcl‐1en
dc.subject.othermelanomaen
dc.subject.othermiRNAen
dc.subject.othersiRNAen
dc.subject.otherTRAILen
dc.titleMcl‐1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cellsen
dc.typeArticleen
dc.type.versionpublishedVersionen
dcterms.bibliographicCitation.doi10.1002/mc.23253en
dcterms.bibliographicCitation.issue11en
dcterms.bibliographicCitation.journaltitleMolecular Carcinogenesisen
dcterms.bibliographicCitation.originalpublishernameWileyen
dcterms.bibliographicCitation.originalpublisherplaceNew York, NYen
dcterms.bibliographicCitation.pageend1268en
dcterms.bibliographicCitation.pagestart1256en
dcterms.bibliographicCitation.volume59en
tub.accessrights.dnbfreeen
tub.affiliationFak. 3 Prozesswissenschaften>Inst. Biotechnologie>FG Angewandte Biochemiede
tub.affiliation.facultyFak. 3 Prozesswissenschaftende
tub.affiliation.groupFG Angewandte Biochemiede
tub.affiliation.instituteInst. Biotechnologiede
tub.publisher.universityorinstitutionTechnische Universität Berlinen
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