Abstract 2874: Treatment with the autophagy inhibitor 3-Methyladenine sensitizes pancreatic cancer cells to GSK3 inhibition-induced apoptosis
Bibliographic record
Abstract
Abstract Pancreatic cancer (PC) is the fourth leading cause of cancer-related death worldwide and has the highest fatality rate of all cancers. The chemoresistance of PC cells contributes to the poor prognosis of PC patients which raises the need for the identification and development of new effective therapy. Studies have revealed that the glycogen synthase kinase 3 (GSK3) is overexpressed in human pancreatic adenocarcinoma as compared to normal pancreas and its inhibition leads to the growth arrest of established tumor xenografts thus suggesting a tumor promoting role for GSK3 in PC cells. Considering that GSK3 inhibitors are currently under clinical trial for treatment of different disorders such as neurodegenerative diseases and diabetes, inhibition of GSK3 activity might represent an attractive therapeutic option for PC patients. However, mechanisms under the control of GSK3 activity in PC cells need to be clarified. We have previously demonstrated that prolonged inhibition of GSK3 activity induces JNK-dependent cell death in human PC cells. Recently, it was suggested in prostate cancer cells that GSK3 promotes both apoptosis and autophagy, the latter playing a protective role against cell death. Interestingly, inhibition of autophagy was shown to sensitize diverse cancer cells to a wide array of stress conditions. The AIM of the study was to evaluate whether GSK3 controls autophagy in PC cells and determine the role of autophagy with regard to PC cell survival. METHODS. Experiments were performed using the human PC cell lines PANC1 and MIAPaCa2. GSK3 activity was inhibited by treatment with a specific GSK3 inhibitor SB216763 (20μM). Apoptosis was measured by assessment of PARP cleavage and caspase 3 and 7 activities. Autophagy was evaluated by the detection of the membrane-bound LC3B-II isoform. The autophagy inhibitor 3-methyladenine 3-MA (10mM) and the JNK inhibitor SP600125 (25μM) were also used. RESULTS. 1) Prolonged inhibition of GSK3 activity (48-72h) in PC cells induced both an apoptotic and autophagic responses. Treatment with 3-MA 2) elicited an apoptotic response and 3) strongly promoted the SB216763-induced apoptosis. 4) Mechanistically, inhibition of GSK3 activity led to a rapid and persistent activation of the JNK-cJun pathway. 5) Interestingly, blockade of the JNK pathway prevented the SB216763-induced apoptosis but not the SB216763-induced autophagy. CONCLUSION. Our results provide evidences that GSK3 regulates both apoptosis and autophagy in PC cells. On one hand, inhibition of GSK3 activity triggers apoptosis through JNK-dependent mechanisms. On the other hand, inhibition of GSK3, independently of the JNK pathway, promotes autophagy, a process that appears to protect PC cells against cell death. Inhibition of autophagy might represent an attractive avenue to promote cytotoxic activity of potential therapeutic agents such as GSK3 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2874. doi:10.1158/1538-7445.AM2011-2874
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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) | 0.001 | 0.001 |
| 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) | 0.004 | 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".