The mTOR Targets 4E-BP1/2 Restrain Tumor Growth and Promote Hypoxia Tolerance in PTEN-driven Prostate Cancer
Bibliographic record
Abstract
Abstract The mTOR signaling pathway is a central regulator of protein synthesis and cellular metabolism in response to the availability of energy, nutrients, oxygen, and growth factors. mTOR activation leads to phosphorylation of multiple downstream targets including the eukaryotic initiation factor 4E (eIF4E) binding proteins-1 and -2 (EIF4EBP1/4E-BP1 and EIF4EBP2/4E-BP2). These binding proteins inhibit protein synthesis, but are inactivated by mTOR to stimulate cell growth and metabolism. However, the role of these proteins in the context of aberrant activation of mTOR, which occurs frequently in cancers through loss of PTEN or mutational activation of the PI3K/AKT pathway, is unclear. Here, even under conditions of aberrant mTOR activation, hypoxia causes dephosphorylation of 4E-BP1/4E-BP2 and increases their association with eIF4E to suppress translation. This is essential for hypoxia tolerance as knockdown of 4E-BP1 and 4E-BP2 decreases proliferation under hypoxia and increases hypoxia-induced cell death. In addition, genetic deletion of 4E-BP1 and 4E-BP2 significantly accelerates all phases of cancer development in the context of PTEN loss–driven prostate cancer in mice despite potent PI3K/AKT and mTOR activation. However, even with a more rapid onset, tumors that establish in the absence of 4E-BP1 and 4E-BP2 have reduced levels of tumor hypoxia and show increased cell death within hypoxic tumor regions. Together, these data demonstrate that 4E-BP1 and 4E-BP2 act as essential metabolic breaks even in the context of aberrant mTOR activation and that they are essential for the creation of hypoxia-tolerant cells in prostate cancer. Mol Cancer Res; 16(4); 682–95. ©2018 AACR.
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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 | 0.001 | 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) | 0.002 | 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 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".