Abstract 3298: Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1)
Why this work is in the frame
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Bibliographic record
Abstract
Abstract 3,3’-diindolylmethane (DIM) and its halogenated derivatives (ring-DIMs) are recently shown to induce protective autophagy in human prostate cancer cells. The mechanism of induction of autophagy by DIM has not been elucidated. As DIM is a mitochondrial ATP synthase inhibitor, we hypothesized that DIM and ring-DIMs induce autophagy via alteration of AMP/ATP ratio and activation of AMPK signaling in prostate cancer cells. Autophagic activity was monitored by LC3B-I to LC3B-II conversion in LNCaP and C42B prostate cancer cells. Autophagic vacuoles were examined using Cyto-ID autophagy detection kit and transmission electron microscope (TEM). Protein levels for AMPK, pAMPK, acetyl-CoA carboxylase (ACC), pACC, AEG-1, pULK-1 and β-actin were measured by western blot. AMPK and AEG-1 gene expression was downregulated using siRNA. DIM and ring-DIMs induced autophagy by increasing autophagic vacuoles and LC3B-I to LC3B-II conversion in LNCaP and C42B cells. These compounds also induced AMPK, ULK-1 and ACC phosphorylation in a time dependent manner. Interestingly, DIM, 4,4’ dibromoDIM and 7,7’ dichloroDIM induced the oncogenic protein AEG-1 time dependently in LNCaP and C42B cells. Downregulation of AEG-1 or AMPK inhibited DIM- and ring-DIM-induced autophagy. Pretreatment with ULK1 inhibitor MRT 67307 or siRNAs targeting AEG-1 or AMPK potentiated the cytotoxicity of DIM and ring-DIMs. Interestingly, downregulation of AEG-1 induced senescence in cells treated with toxic concentrations of DIM or ring-DIMs, and inhibited the onset of apoptosis in response to DIM or ring-DIMs. In summary, we identified a novel mechanism for DIM- and ring-DIM-induced protective autophagy, via induction of AEG-1 and activation of AMPK. Our findings could help towards the development of novel drug therapies for prostate cancer that include selective autophagy inhibitors as adjuvants. Citation Format: Hossam Draz, Alexander Goldberg, Thomas Sanderson, Stephen Safe. Diindolylmethane and its halogenated analogues induce autophagy in human prostate cancer cells via induction of the astrocyte-elevated gene-1 (AEG-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3298. doi:10.1158/1538-7445.AM2017-3298
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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 | 0.001 | 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) | 0.000 | 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