Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM.

ABSTRACT: A large proportion of melanomas harbour the activating BRAF^V600E mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAF^V600E kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM. Apoptosis could be significantly augmented when PLX4032 was combined with an inhibitor of the pro-survival protein BCL-XL, whereas neutralization of the pro-survival family member BCL-2 caused no additional cell death. Although the initial response to PLX40

SUBMITTER: Rohrbeck L 

PROVIDER: S-EPMC5136498 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature