Degradation of AMPK‐α1 sensitizes BRAF inhibitor‐resistant melanoma cells to arginine deprivation
| العنوان: | Degradation of AMPK‐α1 sensitizes BRAF inhibitor‐resistant melanoma cells to arginine deprivation |
|---|---|
| المؤلفون: | Macus Tien Kuo, Miguel Suarez, Xiaoqing Han, Sumedh S. Shah, Medhi Wangpaichitr, Ying-Ying Li, Niramol Savaraj, Chunjing Wu, Shu Mei Chen, Lynn G. Feun, Jeffrey S. Prince |
| المصدر: | Molecular Oncology, Vol 11, Iss 12, Pp 1806-1825 (2017) Molecular Oncology |
| بيانات النشر: | Wiley, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Proto-Oncogene Proteins B-raf, Cancer Research, Proteasome Endopeptidase Complex, autophagy, Arginine, Ubiquitin-Protein Ligases, Mice, Nude, Apoptosis, AMP-Activated Protein Kinases, lcsh:RC254-282, 03 medical and health sciences, Downregulation and upregulation, Cell Line, Tumor, Genetics, medicine, Animals, Humans, metabolic reprogramming, Protein kinase B, Melanoma, Protein Kinase Inhibitors, Ubiquitins, Research Articles, biology, MEK inhibitor, Autophagy, Glucose transporter, ubiquitin‐proteasome system, General Medicine, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, AMPK‐α1, DNA-Binding Proteins, 030104 developmental biology, Oncology, E3 ubiquitin ligase, Drug Resistance, Neoplasm, BRAF inhibitor‐resistant melanoma, Proteolysis, Cancer research, biology.protein, Molecular Medicine, GLUT1, Female, Research Article |
| الوصف: | Melanomas harboring BRAF mutation (V600E) are known to recur frequently following treatment with BRAF inhibitors (BRAFi) despite a high initial response rate. Our previous study has uncovered that BRAFi-resistant melanoma (BR) cells are vulnerable to arginine deprivation. It has been reported that naive melanoma cells undergo autophagy and re-express argininosuccinate synthetase 1 (ASS1) to enable them to synthesize arginine for survival when encountering arginine deprivation. Abolishing these two factors in BR cells confers sensitivity to arginine deprivation. In this report, we further demonstrated that downregulation of AMPK-α1 in BR cells is a major factor contributing to impairment of autophagy as evidenced by decreased autophagosome formation. These BR cells also showed a metabolic shift from glucose to arginine dependence, which was supported by decreased expressions of GLUT1 (glucose transporter) and hexokinase II (HKII) coupled with less glucose uptake but high levels of arginine transporter CAT-2 expression. Furthermore, silencing CAT-2 expression also distinctly attenuated BR cell proliferation. Notably, when naive melanoma cells became BR cells by long-term exposure to BRAFi, a stepwise degradation of AMPK-α1 was initiated via ubiquitin-proteasome system (UPS). We discovered that a novel E3 ligase, RING finger 44 (RNF44), is responsible for promoting AMPK-α1 degradation in BR cells. RNF44 expression in BR cells was upregulated by transcription factor CREB triggered by hyperactivation of ERK/AKT. High levels of RNF44 corresponding to low levels of AMPK-α1 appeared in BR xenografts and melanoma tumor samples from BR and BRAFi/MEK inhibitor (MEKi)-resistant (BMR) melanoma patients. Similar to BR cells, BMR cells were also sensitive to arginine deprivation. Our study provides a novel insight into the mechanism whereby BRAFi or BRAFi/MEKi resistance drives proteasomal degradation of AMPK-α1 and consequently regulates autophagy and metabolic reprogramming in melanoma cells. |
| اللغة: | English |
| تدمد: | 1574-7891 1878-0261 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bbe0b1b044b0c2aa755846d584b6d3cfTest https://doaj.org/article/0ce0038e157442c390f27ac569a49769Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bbe0b1b044b0c2aa755846d584b6d3cf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15747891 18780261 |
|---|