Abstract LB-133: A novel tumor suppressor role for sirt1 inhibiting mitophagy in prostate mouse tissue.
Bibliographic record
Abstract
Abstract Introduction. Sirtuin family consists of NAD+-dependent class III histone deacetylases (HDACs). Sirtuin family members (SIRT1-SIRT7) were shown to regulate a variety of physiopathological process, including aging, cellular proliferation, metabolism, and autophagy. Prior studies report SIRT1 as either an oncogene or a tumor suppressor depending upon the cell type and system. However, a reduced expression of SIRT1 in prostate cancer has been reported, supporting the view of SIRT1 as a tumor suppressor. Deregulated intracellular reactive oxygen species (ROS) production induces oxidative stress and damage of nucleic acids, proteins and lipids and may contribute to tumorigenesis. Herein, we provide in vivo support for SIRT1 as a tumor suppressor in prostate cancer. The mechanism appears to involve SIRT1-mediated inhibition of A) mitochondrial ROS production and B) mitophagy. Materials and methods. 7 month old Sirt1 transgenic mice were used. To investigate the molecular mechanisms through which SIRT1 regulate mitochondrial ROS production and mitophagy process, 3T3 cells wild type (Sirt1+/+) and SIRT1 knockout (Sirt1-/-) were used. Results. Our clinical and experimental data show a decrease in both SIRT1 expression associated with reduced patient survival probability. A histological evaluation of the H&E performed on both Sirt1+/+ and Sirt1-/- mouse prostate tissues demonstrates that there is a focal atypical intraductal proliferation in prostatic glands of the Sirt1-/- mice, compatible with high grade prostatic intraductal neoplasia (HGPIN). The IHC and relative quantitation of the mouse prostate tissues with Ki67 and AMACR, which are a proliferative and PIN marker respectively, showed an increase of both markers in Sirt1-/- mouse prostate tissue. Preliminary data generated from Sirt1+/+ and Sirt1-/- 3T3 cells suggest that SIRT has a key role in maintaining the mitochondrial healthy status regulating ROS. Sirt1-/- cells undergo a higher oxidative stress, which can lead to cellular damage. We also found mitophagy markers; Beclin1, Bnip3l and LC3 to be overexpressed in Sirt1-/- mouse prostate tissues. Conclusion and future prospects. These studies suggest SIRT1 inhibits PIN in vivo. The molecular mechanism through which SIRT1 works in a tumor suppressor way is still unknown. We propose a loss of SIRT1 expression may alter the oxidative environment, thereby promoting PIN. Citation Format: Gabriele Di Sante, Liping Wang, Chenguang Wang, Sara Bisetto, Mathew C Casimiro, Michael Powell, Michael McBurney, Richard Pestell. A novel tumor suppressor role for sirt1 inhibiting mitophagy in prostate mouse tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-133. doi:10.1158/1538-7445.AM2013-LB-133
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 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) | 0.003 | 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".