A277 DNA-PK SUSTAINS AUTOPHAGY AND PANCREATIC CANCER CELL GROWTH
Bibliographic record
Abstract
Pancreatic cancer (PDAC) is currently the 4th leading cause of cancer related deaths in Canada. The life expectancy with metastatic PDAC is 3–6 months. Malignant pancreatic tumours are one of the most intrinsically resistant tumours that can withstand majority of the currently available treatment modalities. The tumours are showing resistance to Gemcitabine, the most commonly prescribed drug. Gemcitabine is known to induce DNA damage that, if not repaired, lead to cell death. Of note, it was observed that PDAC tissues display higher expression of DNA-PKcs, the catalytic subunit of DNA-PK involved in DNA repair, suggesting that DNA-PKcs and/or DNA-PK could provide a growth advantage to PDAC cells. Still, the role of DNA-PK in pancreatic pathophysiology remains elusive. Studies in the recent years have validated the high-basal levels of autophagy in PDAC cells and proven its importance in sustaining cell growth. It is noteworthy that agents inducing DNA damage have been correlated with autophagy modulation suggesting a potential link between autophagy-DNA damage and/or DNA repair mechanisms. However, the underlined mechanisms have yet to be identified. The overall objective was to interrogate a potential role for DNA-PK, increased in PDAC tissues, in regulating autophagy and growth of PDAC cells. The PDAC cell line MiaPaCa-2 was used. The specific inhibitor NU7441 was used to block DNA-PK activity. Cell counting and clonogenic assays were performed to assess cell growth. Autophagic flux was measured by co-treatment with the autophagy inhibitor Bafilomycin A1. 1) We observed a dose- and time-dependent decrease in cell number in DNA-PK inhibited cells as compared to control cells. 2) This coincides with the reduced colony forming ability of PDAC cells when treated with NU7441. 3) The impact on cell growth correlated with induction of cell apoptosis as measured by PARP and caspase-7 cleavage. 4) Given the reported role of autophagy in sustaining PDAC cell growth, we assessed the impact of DNA-PK inhibition on autophagy. Immunoblotting and immunofluorescence studies revealed that NU7441 treatment triggers increased expression of the autophagy receptor p62/SQSTM1 as well as lipidation of LC3B indicative of autophagy modulation. 5) Autophagy flux measurement supported blockade of autophagy upon DNA-PK inhibition. Taken together, our results demonstrate that interference with DNA-PK activity is an attractive avenue to abrogate PDAC cell growth. Our observations support a novel role for DNA-PK in regulating autophagy. Given that PDAC tissues were shown to display high expression levels of DNA-PKcs, it is tempting to speculate that DNA-PK could be involved in maintaining high basal levels of autophagy as observed in PDAC cells. NSERC, CRS
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".