Alterations of ROS generation and drug sensitivity in Ras-transformed pancreatic cells
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Bibliographic record
Abstract
3544 Background. Increased level of reactive oxygen species (ROS), which is known to stimulate cell proliferation through signal transduction, has been observed in a wide spectrum of human cancers. Previous studies suggested that there is an association between ROS generation and oncogenic signal involving Ras, which seems to affect the activity of the plasma membrane associated redox enzyme NADPH oxidase (NOX). However, the mechanisms responsible for such oxidative stress in Ras-transformed cancer cells are still unclear, and the potential therapeutic implications remain to be investigated. Methods and Results. By using a variety of biochemical and molecular biology methods including flow cytometry analysis of intracellular ROS, immuoflorescence microscopy and electrophoresis analysis of protein expression, enzyme assay of NOX activity, and matrigel assays for cell motility and invasion, we investigated the biochemical and molecular events involved in Ras transformation and production of ROS. We found that the K-Ras transformed pancreatic cells produced significantly higher level of ROS, which stimulated cell growth and motility, and was associated with an upregulation of superoxide dismutase (SOD) expression, likely as an protective mechanism in response to the ROS stress. Further studies revealed that K-Ras transformation led to increased level of PtdIns(3,4,5)P3 and activation of AKT. The increase of PtdInsP3 seemed to promote the assembling of active NOX enzyme complex, leading to increased production of superoxide radical. Interestingly, capsaicin, a compound previously known to interact with NOX, was able to induce a dramatic accumulation of ROS and cause a preferential cytotoxicity in the transformed cells compared to the non-malignant cells, as evidenced by morphological change, inhibition of motility and invasiveness, and suppression of cell proliferation. Conclusion. Our results suggested that Ras oncogenic signal induced consititutive activation of NOX by activation of PI3-kinase pathway in cancer cells, leading to an increase in free radical generation and preferential vulnerability to further ROS stress by targeting NOX with capsaicin.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it