Back to Search
Start Over
Trametinib potentiates TRAIL‐induced apoptosis via FBW7‐dependent Mcl‐1 degradation in colorectal cancer cells
- Source :
- Journal of Cellular and Molecular Medicine
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- Trametinib is a MEK1/2 inhibitor and exerts anticancer activity against a variety of cancers. However, the effect of Trametinib on colorectal cancer (CRC) is not well understood. In the current study, our results demonstrate the ability of sub‐toxic doses of Trametinib to enhance TRAIL‐mediated apoptosis in CRC cells. Our findings also indicate that Trametinib and TRAIL activate caspase‐dependent apoptosis in CRC cells. Moreover, Mcl‐1 overexpression can reduce apoptosis in CRC cells treated with Trametinib with or without TRAIL. We further demonstrate that Trametinib degrades Mcl‐1 through the proteasome pathway. In addition, GSK‐3β phosphorylates Mcl‐1 at S159 and promotes Mcl‐1 degradation. The E3 ligase FBW7, known to polyubiquitinate Mcl‐1, is involved in Trametinib‐induced Mcl‐1 degradation. Taken together, these results provide the first evidence that Trametinib enhances TRAIL‐mediated apoptosis through FBW7‐dependent Mcl‐1 ubiquitination and degradation.
- Subjects :
- 0301 basic medicine
Proteasome Endopeptidase Complex
F-Box-WD Repeat-Containing Protein 7
Pyridones
Colorectal cancer
Down-Regulation
TRAIL
Pyrimidinones
TNF-Related Apoptosis-Inducing Ligand
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Trametinib
Cell Line, Tumor
hemic and lymphatic diseases
medicine
Humans
Phosphorylation
neoplasms
degradation
Proteasome Pathway
Glycogen Synthase Kinase 3 beta
biology
Chemistry
apoptosis
Ubiquitination
Original Articles
Cell Biology
medicine.disease
Ubiquitin ligase
030104 developmental biology
Mcl‐1
Apoptosis
030220 oncology & carcinogenesis
Proteolysis
biology.protein
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
Molecular Medicine
Original Article
Colorectal Neoplasms
Protein Binding
Subjects
Details
- ISSN :
- 15824934 and 15821838
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular and Molecular Medicine
- Accession number :
- edsair.doi.dedup.....74c39967c2c6e669dda5e1bd02f7814e