Abstract 4265: Transient versus permanent autophagy inhibition in pancreatic ductal adenocarcinoma
| Autor: | Jane B. Pearce, Ciara H. O'Flanagan, Stephen D. Hursting |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Cancer Research. 79:4265-4265 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, with a 5- year survival rate of less than 5 percent. KRAS-driven PDACs often exhibit increased dependence on autophagy, a process by which cells degrade internal components to mobilize energy stores. When faced with cellular stress, such as nutrient deprivation, tumor growth may initially slow in response to decreasing supplies of growth factors and cytokines. Under these conditions, the induction of autophagy can enable continued tumor growth even in the presence of nutrient stress. Therefore, we posited that nutrient restriction in combination with autophagy inhibition would synergistically disrupt aberrant metabolic pathways and more effectively stunt PDAC tumor progression. To determine the impact of transient autophagy inhibition, cells were treated with 10 μM of the pharmaceutical agent chloroquine (CQ) for 48 hours. To modulate growth factor/cytokine signaling as well as nutrient sensing signaling serum and glucose restriction were used in vitro. Next, permanent autophagy ablation was achieved through CRISPR/Cas9 technology, autophagy related 5 (Atg5) was deleted in Panc02 cells generating an autophagy-deficient (Atg-/-) PDAC cell line. Growth kinetics were determined in a range of culture matrixes to determine the proliferation rate, invasiveness, and anchorage independence of cells. The combination of CQ and nutrient stress elicited an additive effect on cellular proliferation in both murine and human-derived KRAS mutant PDAC cells (Panc02 and MIA PaCa-2 respectively). In contrast, Atg5-/- Panc02 cells did not display any alteration in cellular proliferation in vitro. Atg5 deletion resulted in decreased expression of mesenchymal markers N-Cadherin and Snail as well as decreased invasiveness and anchorage independent colony formation. Upon intrapancreatic injection in a syngeneic model, Atg-/- cells exhibited reduced tumor growth relative to control Atg5+/+cells, indicating the compensatory mechanisms effective in vitro failed to protect these cells in vivo. Thus, our findings reveal a potential synergism between autophagy inhibition and nutrient stress in PDAC. Citation Format: Jane B. Pearce, Ciara H. O'Flanagan, Stephen D. Hursting. Transient versus permanent autophagy inhibition in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4265. |
| Databáze: | OpenAIRE |
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