Dependence of malignant proliferation associated with loss of PTEN on glucose concentration in the hyperglycemic range: Relevance to population studies linking hyperglycemia to unfavorable cancer prognosis
Bibliographic record
Abstract
11113 Background: Loss of function of the tumor suppressor PTEN enhances malignant proliferation, but effects on cellular energy metabolism are less well characterized. Population studies show that the metabolic syndrome (characterized by hyperglycemia, hyperinsulinism, and obesity) is increasingly prevalent in affluent societies and is associated with adverse outcome of many cancers, but the molecular basis for this is poorly understood. Methods: We used a tetracycline-inducible PTEN expression vector in the PTEN-null U251 glioma cell line to characterize effects of PTEN on cellular energy metabolism. Results: Forced expression of PTEN led to decreased phospho-AKTSer473, decreased hexokinase II and HIF-1 alpha levels, and increased p53 levels. While proliferation of PTEN-positive cells was insensitive to variation in glucose concentration at levels higher than 2.5 mM, PTEN-null cells significantly increased proliferation with increasing glucose concentration across normal physiologic range to ∼10 mM. PTEN-null cells consumed more glucose than PTEN-positive cells (17.2 ± 2.0 vs. 8.8 ± 1.5 mM/million cells/48 hrs) and produced more lactate (35.9 ± 4.8 vs. 10.7 ± 2.3 mM/million cells/48 hrs). When cells were incubated in presence of 2-deoxy-glucose (2-DG), growth inhibition was greater for PTEN-null cells (47.4% inhibition relative to control without 2-DG) compared with PTEN-positive cells (10.8% inhibition relative to control without 2-DG). Conclusions: Loss of function of PTEN leads to increased glycolysis, and increased dependence on glucose availability. Only in the presence of glucose in the hyperglycemic range are maximal adverse effects of loss of PTEN on cellular proliferation and survival seen. This provides a novel mechanism to explain at least in part the relationship between hyperglycemia and cancer mortality observed in several large population studies. The data also suggest that PTEN status is relevant to selection of tumors likely to respond to experimental therapies that exploit glucose dependency. No significant financial relationships to disclose.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".