Inhibition of pancreatic cancer progression through EMT inhibition and induction of ER stress
Pancreatic cancer is a devastating disease with a current overall 5-year survival rate of only 10%, making it the deadliest cancer. The dismal treatment outcome of pancreatic cancer is largely attributed to its highly metastatic and chemo-resistant nature. Cancer cell epithelial to mesenchymal transition (EMT) contributes importantly to cell invasion, metastasis, and drug resistance in pancreatic cancer. In addition, pancreatic cancer cells exhibit an elevated basal level of unfolded protein response (UPR) signaling for survival, due to increased cellular endoplasmic reticulum (ER) stress under hypoxia. Inhibiting EMT and aggravating ER stress both pose as promising approaches to improve pancreatic cancer treatment. However, the relationship between ER stress and cancer cell EMT has not yet been fully understood. We previously reported a high throughput screening (HTS) study aiming to find small molecule inhibitors for EMT in pancreatic cancer cells. This dissertation documents our investigation on the top hit compound (namely C150) for its activities and mechanisms in inhibiting pancreatic cancer cell EMT, suppressing cell invasion, inducing ER stress, and reducing tumor growth in mice. These studies also discovered a mechanistic link between ER stress and pancreatic cancer cell EMT. We investigated the activities of C150 in inhibiting pancreatic cancer cell invasion and the mechanism of EMT inhibition (Chapter 4). C150 exhibited well-separated cytotoxicity between pancreatic cancer cells and non-cancerous cells. The IC50 values were 1~2.5 mM in multiple pancreatic cancer cell lines and 12.5 mM in non-cancerous pancreatic epithelial cells. C150 significantly inhibited pancreatic cancer cell migration and invasion in both 3-dimensional (3D) cell invasion assays and 2-dimensional (2D) wound scratching assays and Boyden chamber trans-well migration-invasion assays. Moreover, C150 treatment decreased matrix metallopeptidase-2 (MMP-2) and matrix metallopeptidase-9 (MMP-9) gene expressions in pancreatic cancer cells ....
Medienart: |
E-Book |
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Erscheinungsjahr: |
2021 |
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Erschienen: |
Erscheinungsort nicht ermittelbar: University of Kansas ; 2021 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Wang, Tao [VerfasserIn] |
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Hochschulschrift: |
Links: |
hdl.handle.net [kostenfrei] |
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Weitere IDs: |
1808/31785 |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
1828088404 |
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