Abstract 276: Mir-139 regulates autophagy in prostate cancer cells through Beclin-1 and mTOR signaling proteins
Bibliographic record
Abstract
Abstract Background: Prostate cancer represents the second leading cause of cancer death in men and develops as a result of the accumulation of genetic and epigenetic alterations. We previously identified a panel of five miRNAs associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using NGS-based whole miRNome sequencing and qPCR-based validation analysis. We have shown that expression of miR-139, one of the downregulated miRNAs from this panel, was associated with improved prognosis in patients with localized prostate cancer. Furthermore, miR-139 overexpression inhibited prostate cancer cell growth through signaling pathways mediated in part through downregulation of AXL and IGF1R. Here, we further investigated the molecular mechanisms by which miR-139 could inhibit prostate cancer cell growth. Methods: We examined miR-139 transfected PC3, DU145 and LNCaP cells by morphology as well as by cell-based assays, confocal microscopy and immunoblotting. Results and Discussion: We found that treatment of prostate cancer cells with miR-139 resulted in phenotypic changes characteristic of autophagic cells. Conversion of the microtubule-associated protein light chain 3 (LC3-I to LC3-II) was used to monitor autophagy. We observed that the treatment of PC3 and LNCaP cells with miR-139 increased the conversion of LC3-I to LC3-II protein that was specifically inhibited by addition of miR-139 antagomir. The upregulation of LC3 II was further confirmed by confocal microscopy of PC3 cells treated with miR-139. Mammalian target of rapamycin (mTOR) and Beclin1 are two important autophagy-related molecules playing significant roles in different stages. mTOR negatively regulates autophagy machinery. Treatment of cells with miR-139 inhibited both activation and expression of mTOR. We also observed increased levels of phospho-Beclin 1 in PC3 cells treated with mir-139. Beclin 1 is a scaffold protein that assembles components for promoting or inhibiting autophagy and its phosphorylation controls autophagy. The cargo adaptor protein, p62/SQSTM1, interacts with autophagic substrates, delivering them to the autophagosome for degradation, and is degraded during autophagy. We found that during early treatment of cells with miR-139, p62 expression is inhibited, while at later stages, p62 expression accumulates, suggesting that autophagic flux may be blocked. These results suggest that miR-139 is regulating autophagy in prostate cancer cells at least in part through the mTOR and Beclin-1 proteins. Citation Format: Tania C. Benatar, Robert Nam, Christopher Sherman, Yutaka Amemiya, Arun Seth. Mir-139 regulates autophagy in prostate cancer cells through Beclin-1 and mTOR signaling proteins [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 276.
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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) | 0.003 | 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".