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JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
Oncogenic BRAF inhibitor UAI-201 induces cell cycle arrest and autophagy in BRAF mutant glioma cells.
Life Sciences 2014 May 29
AIMS: An activating mutation of BRAF (BRAF-V600E) has been reported in a subset of malignant brain tumors. Thus, the aim of the present study was to identify the antiproliferative effect of the new oncogenic B-Raf targeting drug UAI-201 on 6 types of glioma cell lines with differing B-Raf mutational status.
MAIN METHODS: The IC50 values of UAI-201 were determined using crystal violet assays in six glioma cell lines. Real-time RT-PCR was performed to assess the functional role of multidrug resistance proteins in response to UAI-201. The effects of UAI-201 on six glioma cells were further examined by immunoblotting analysis, cell cycle analysis, flow cytometric apoptotic assay and autophagy assay. To identify the role of autophagy in UAI-201-induced growth inhibition, Atg5 and Beclin 1 were knocked down by RNA interference.
KEY FINDINGS: Real-time RT-PCR analysis showed a poor correlation between UAI-201 activity and the expression level of multidrug resistance proteins. The growth inhibitory effects of UAI-201 correlated with the BRAF-V600E genotype of the glioma cell lines. BRAF blockade with UAI-201 resulted in dose-dependent inhibition of MEK/ERK phosphorylations and increased G0/G1 arrest in glioma cells with BRAF-V600E. Interestingly, UAI-201 preferentially induced autophagy in BRAF-V600E cells, but not in BRAF-WT cells. More notably, autophagy inhibition through siRNA-mediated Beclin 1 knockdown partially attenuated the growth inhibition induced by UAI-201 in BRAF-V600E cells.
SIGNIFICANCE: The pro-death autophagic processes could be one of the underlying mechanisms for the sensitization of BRAF-V600E glioma cells toward UAI-201.
MAIN METHODS: The IC50 values of UAI-201 were determined using crystal violet assays in six glioma cell lines. Real-time RT-PCR was performed to assess the functional role of multidrug resistance proteins in response to UAI-201. The effects of UAI-201 on six glioma cells were further examined by immunoblotting analysis, cell cycle analysis, flow cytometric apoptotic assay and autophagy assay. To identify the role of autophagy in UAI-201-induced growth inhibition, Atg5 and Beclin 1 were knocked down by RNA interference.
KEY FINDINGS: Real-time RT-PCR analysis showed a poor correlation between UAI-201 activity and the expression level of multidrug resistance proteins. The growth inhibitory effects of UAI-201 correlated with the BRAF-V600E genotype of the glioma cell lines. BRAF blockade with UAI-201 resulted in dose-dependent inhibition of MEK/ERK phosphorylations and increased G0/G1 arrest in glioma cells with BRAF-V600E. Interestingly, UAI-201 preferentially induced autophagy in BRAF-V600E cells, but not in BRAF-WT cells. More notably, autophagy inhibition through siRNA-mediated Beclin 1 knockdown partially attenuated the growth inhibition induced by UAI-201 in BRAF-V600E cells.
SIGNIFICANCE: The pro-death autophagic processes could be one of the underlying mechanisms for the sensitization of BRAF-V600E glioma cells toward UAI-201.
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