Related Experiment Video
Updated: Sep 5, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma
Yinu Zhao1, Yue Wang2, Li Zhang1
1Eye Center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Melanoma with a BRAF mutation is more common to develop into a fatal disease. BRAF mutation inhibitor-induced autophagy affects the drug efficacy in many cancer types. The role of autophagy during BRAF inhibition in uveal melanoma (UM) remains unclear. In this study, we examined the autophagic flux and compared the number of autophagic vacuoles during the BRAF inhibition in UM. The PKR-like endoplasmic reticulum (ER) kinase (PERK) arm was studied to test whether the ER stress was involved. The effects of downregulation of ER stress by targeting the PERK arm (pharmacologically and genetically) were also assessed. We found a dose-dependent increase of autophagic flux in OCM1A cells during the BRAF inhibition. This phenomenon was further verified by an enhanced number of GFP-LC3 puncta and was finally confirmed by raised autophagic index examined by transmission electron microscopy. Pathway analysis revealed that the vemurafenib (the BRAF inhibitor)-induced autophagy was independent of the MAPK signaling pathway. Instead, it was possibly regulated via the enhanced ER stress response. We further found that the inhibition of ER stress response rescued cell death. Therefore, our results suggest BRAF inhibition promotes ER stress response-induced autophagy in UM. Targeting ER stress response can partially revert autophagy and rescue cell death, which may impair the anti-tumor effect of BRAF inhibitor in UM.
Insights
BRAF inhibitors trigger autophagy and endoplasmic reticulum (ER) stress in uveal melanoma (UM). Targeting ER stress may reverse autophagy and cell death, potentially impacting BRAF inhibitor efficacy in UM treatment.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- BRAF mutations are common in fatal melanomas.
- BRAF inhibitor-induced autophagy impacts drug efficacy across cancers.
- The role of autophagy in BRAF inhibition within uveal melanoma (UM) is not well understood.
Purpose of the Study:
- To investigate the role of autophagy and endoplasmic reticulum (ER) stress during BRAF inhibition in UM.
- To examine autophagic flux and autophagic vacuoles in UM cells under BRAF inhibition.
- To determine if the PKR-like endoplasmic reticulum (ER) kinase (PERK) pathway is involved in ER stress.
Main Methods:
- Assessed autophagic flux and autophagic vacuoles in OCM1A cells treated with BRAF inhibitor.
- Utilized GFP-LC3 puncta and transmission electron microscopy to quantify autophagy.
- Investigated the involvement of the PERK arm of the ER stress response.
- Evaluated the effects of targeting the PERK arm pharmacologically and genetically.
Main Results:
- BRAF inhibition led to a dose-dependent increase in autophagic flux in OCM1A cells.
- Enhanced GFP-LC3 puncta and an increased autophagic index confirmed increased autophagy.
- Vemurafenib-induced autophagy was independent of the MAPK signaling pathway.
- Autophagy appeared to be regulated by enhanced ER stress response.
- Inhibiting the ER stress response rescued cell death.
Conclusions:
- BRAF inhibition in UM promotes autophagy via an enhanced ER stress response.
- Targeting the ER stress response can partially reverse autophagy and rescue cell death.
- This interplay may affect the anti-tumor efficacy of BRAF inhibitors in UM.
More Related Videos
05:46Implantation and Evaluation of Melanoma in the Murine Choroid via Optical Coherence Tomography
Published on: December 2, 2022
08:18Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma
Published on: September 8, 2021
