Back to Search
Start Over
Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress.
- Source :
-
Cancer research [Cancer Res] 2008 Aug 15; Vol. 68 (16), pp. 6708-17. - Publication Year :
- 2008
-
Abstract
- We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress-induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1-deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Up-regulation of Mcl-1 was also due to increased transcription that involved the IRE1alpha and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress.
- Subjects :
- Activating Transcription Factor 6 genetics
Activating Transcription Factor 6 metabolism
Antiviral Agents pharmacology
Apoptosis Regulatory Proteins genetics
Apoptosis Regulatory Proteins metabolism
Blotting, Western
Endoribonucleases genetics
Endoribonucleases metabolism
Enzyme Inhibitors pharmacology
Flow Cytometry
Humans
Melanoma metabolism
Membrane Potential, Mitochondrial
Myeloid Cell Leukemia Sequence 1 Protein
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 genetics
RNA, Messenger genetics
RNA, Messenger metabolism
RNA, Small Interfering pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Skin Neoplasms metabolism
Thapsigargin pharmacology
Transcription, Genetic
Transfection
Tumor Cells, Cultured
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Tunicamycin pharmacology
Up-Regulation
Apoptosis physiology
Endoplasmic Reticulum physiology
Melanoma pathology
Oxidative Stress
Proto-Oncogene Proteins c-bcl-2 metabolism
Skin Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 18701495
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-0349