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Combinations of Tyrosine Kinase Inhibitor and ERAD Inhibitor Promote Oxidative Stress-Induced Apoptosis through ATF4 and KLF9 in Medullary Thyroid Cancer
- Publication Year :
- 2018
-
Abstract
- Medullary thyroid carcinoma (MTC) originates from the C cells of the thyroid gland, which secrete calcitonin. Lymph node and distant metastases are frequently present at diagnosis. Activating mutations of RET, a driver oncogene in MTC that encodes a tyrosine kinase receptor, prevents apoptosis through inhibition of ATF4, a key transcriptional regulator of endoplasmic reticulum (ER) stress. We hypothesized that the combination of a tyrosine kinase inhibitor (TKI) and an ATF4 inducer promotes cell death by triggering catastrophic oxidative stress and apoptotic cell death. Here, we report that the ER-associated protein degradation (ERAD) inhibitor eeyarestatin sensitized MTC cells to the TKIs, sunitinib and vandetanib, thereby leading to synergistic upregulation of ATF4 expression, accumulation of reactive oxygen species, and subsequent cell death. Genome-wide analysis of ATF4 interaction sites by chromatin immunoprecipitation (ChIP) sequencing revealed that among ATF4 target genes was KLF9 (Kruppel-like factor 9), which induces MTC apoptosis. ChIP assays revealed that ATF4 occupancy at the KLF9 promoter was increased in MTC cells treated with eeyarestatin or vandetanib alone and was further enhanced in cells treated with both drugs, leading to increased KLF9 transcription. Depletion of ATF4 by shRNA led to downregulation of KLF9 expression and prevented oxidative stress–induced cell death. Furthermore, we identified ATF4 target genes (LZTFL1, MKNK2, and SIAH1 with known tumor suppressor function) that were synergistically upregulated with the combination of TKI and ERAD inhibitor. Implications: These findings reveal a combination therapy that induces reactive oxygen species–dependent catastrophic cell death through induction of ATF4 and KLF9 transcriptional activity.
- Subjects :
- 0301 basic medicine
Cancer Research
Programmed cell death
medicine.drug_class
Kruppel-Like Transcription Factors
Apoptosis
Protein degradation
Vandetanib
Receptor tyrosine kinase
Tyrosine-kinase inhibitor
Article
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
medicine
Humans
Molecular Biology
Protein Kinase Inhibitors
biology
Chemistry
Medullary thyroid cancer
Endoplasmic Reticulum-Associated Degradation
medicine.disease
Activating Transcription Factor 4
Oxidative Stress
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
biology.protein
Cancer research
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....343791bb0a256950f6a536a67b0b70df