Upregulation of STAT1 transcription activator by an androgen agonist in prostate cancer cells affects intracellular cholesterol esterification
Bibliographic record
Abstract
LB-197 The objective of this work was to determine the effect of an androgen agonist, R1881, on intracellular cholesterol synthesis and esterification within an androgen-dependent prostate cancer cell line. We investigated the activity (using standardized radiolabeled techniques) and expression (Western Blot) of two cholesterol metabolism enzymes, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and acyl-coenzyme A:cholesterol acyltransferase (ACAT), in the LNCaP androgen-dependent prostate cancer cell model and in the PC-3 androgen-independent model for comparison. At the cellular level, when PC-3 and LNCaP cell lysates were examined for free cholesterol and cholesteryl ester content using prepared enzymatic kits, we found a decrease in free cholesterol and an increase in cholesteryl esters in LNCaP cells treated with the androgen receptor agonist R1881, compared to controls. In the PC-3 cells we did not find a change in total cholesterol or in cholesteryl esters upon R1881 treatment. HMG-CoA reductase activity in the LNCaP and PC-3 cells was increased upon androgen stimulation. Furthermore, HMG-CoA reductase protein expression in PC-3 was higher than in LNCaP cells. The increased intracellular cholesteryl ester levels found in R1881-treated LNCaP cells were not associated with an increased in vitro ACAT activity. In contrast, we found an increase in ACAT activity upon androgen stimulation in PC-3 cells. We analyzed the expression of the two ACAT isoforms, ACAT1 and ACAT2 to determine if their protein levels were affected by the R1881 treatment in both cell lines. We found that ACAT2 expression was induced in LNCaP cells treated with R1881. In the case of PC-3, ACAT1 expression was induced when the cells were treated with the androgen agonist. We investigated the mechanism of ACAT1 induction in PC-3 cells and assessed the expression of STAT1α, a transcriptional activator that modulates ACAT1 expression. We found that STAT1α expression and phosphorylation were induced by R1881 treatment in PC-3; thus it is a possible mechanism to account for increased ACAT1 expression in PC-3 cells. Induction of STAT1α activation may lead to an increase in ACAT1 protein expression which was associated with augmented ACAT activity in PC-3 cells. Interestingly this increased ACAT activity was not associated with increased cholesteryl ester accumulation in PC-3 cells treated with R1881, suggesting that other mechanisms such as cholesterol esterases or cholesteryl ester secretion may contribute to cholesteryl ester homeostasis in prostate cells. Taken together, these findings further support the importance of cholesterol metabolism regulation within prostate cancer cells. Furthermore, they also unravel a novel role for STAT1α in prostate cancer metabolism.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".