dc.contributor.author
Peng, Zhe
dc.contributor.author
Gillissen, Bernhard
dc.contributor.author
Richter, Antje
dc.contributor.author
Sinnberg, Tobias
dc.contributor.author
Schlaak, Max S.
dc.contributor.author
Eberle, Jürgen
dc.date.accessioned
2023-09-22T12:40:38Z
dc.date.available
2023-09-22T12:40:38Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/40946
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-40667
dc.description.abstract
Targeting of MAP kinase pathways by BRAF inhibitors has evolved as a key therapy for BRAF-mutated melanoma. However, it cannot be applied for BRAF-WT melanoma, and also, in BRAF-mutated melanoma, tumor relapse often follows after an initial phase of tumor regression. Inhibition of MAP kinase pathways downstream at ERK1/2, or inhibitors of antiapoptotic Bcl-2 proteins, such as Mcl-1, may serve as alternative strategies. As shown here, the BRAF inhibitor vemurafenib and the ERK inhibitor SCH772984 showed only limited efficacy in melanoma cell lines, when applied alone. However, in combination with the Mcl-1 inhibitor S63845, the effects of vemurafenib were strongly enhanced in BRAF-mutated cell lines, and the effects of SCH772984 were enhanced in both BRAF-mutated and BRAF-WT cells. This resulted in up to 90% loss of cell viability and cell proliferation, as well as in induction of apoptosis in up to 60% of cells. The combination of SCH772984/S63845 resulted in caspase activation, processing of poly (ADP-ribose) polymerase (PARP), phosphorylation of histone H2AX, loss of mitochondrial membrane potential, and cytochrome c release. Proving the critical role of caspases, a pan-caspase inhibitor suppressed apoptosis induction, as well as loss of cell viability. As concerning Bcl-2 family proteins, SCH772984 enhanced expression of the proapoptotic Bim and Puma, as well as decreased phosphorylation of Bad. The combination finally resulted in downregulation of antiapoptotic Bcl-2 and enhanced expression of the proapoptotic Noxa. In conclusion, combined inhibition of ERK and Mcl-1 revealed an impressive efficacy both in BRAF-mutated and WT melanoma cells, and may thus represent a new strategy for overcoming drug resistance.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Bcl-2 proteins
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Enhanced Apoptosis and Loss of Cell Viability in Melanoma Cells by Combined Inhibition of ERK and Mcl-1 Is Related to Loss of Mitochondrial Membrane Potential, Caspase Activation and Upregulation of Proapoptotic Bcl-2 Proteins
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
4961
dcterms.bibliographicCitation.doi
10.3390/ijms24054961
dcterms.bibliographicCitation.journaltitle
International Journal of Molecular Sciences
dcterms.bibliographicCitation.number
5
dcterms.bibliographicCitation.originalpublishername
MDPI
dcterms.bibliographicCitation.volume
24
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
36902392
dcterms.isPartOf.eissn
1422-0067