Accumulation of GMI induces endoplasmic reticulum stress and autophagy via promotion of EGFR endocytosis in lung cancer
| Autor: | Hua-Ying Chien, 簡華瑩 |
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| Rok vydání: | 2016 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 104 GMI, a fungal immunomodulatory protein, is cloned and purified from Ganoderma microsporum. GMI exhibits well-known immunomodulatory and anticancer activity. However, the role of EGFR on GMI-induced endoplasmic reticulum (ER) stress and autophagy is unclear. Our previous study has been discovered that GMI effectively prevents lung cancer proliferation in vitro. Lung cancer is a leading cause of cancer-related death in men and women in many countries. EGFR is the cell-surface receptor. The overexpression of EGFR has been observed in >60% of metastatic non-small-cell lung cancer (NSCLC) tumors and correlates with poor prognosis. In this study, we demonstrated that GMI-inhibited cell viability depends on EGFR in NSCLC (including A549 and H226). We found that GMI-induced ER stress-related molecule, ATF4 (a transcription factor actives autophagy), depends on EGFR endocytosis. Moreover, we found that GMI also increased the expression of ATG5 and promoted LC3 conversion, resulting to induction of autophagy flux via EGFR. The activated EGFR becomes internalized and is transported to late endosomes and lysosomes for degradation. EGFR is primarily internalized through clathrin-mediated endocytosis. Furthermore, ATF4-knockdown abolished ER stress-mediated expression ATG5 and LC3-II, indicating that ER stress downstream pathway mediates the autophagy process. Moreover, Knockdown clathrin suppressed GMI-induced ER stress and autophagy-related molecules. Therefore, we suggested that autophagy could be induced by unfolded protein response (UPR), the major endoplasmic reticulum (ER) stress pathway. In conclusion, GMI induced ER stress-mediated autophagy via promotion of clathrin-mediated EGFR endocytosis in lung cancer. Furthermore, GMI is potential as an anti-cancer drug for NSCLC patients with expressing EGFR. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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