Abstract 5096: Alterations in cholesterol regulation contribute to the production of intratumoral androgens in castration-resistant prostate cancer
Bibliographic record
Abstract
Abstract BACKGROUND: Prostate cancer (CaP) is the most commonly diagnosed cancer and third leading cause of cancer-related death in North American males. Recent evidence suggests that androgens mediate disease progression as recurrent CaP tumors contain androgens in levels high enough to activate the androgen receptor (AR). We have previously shown that in the absence of exogenous androgens, CaP cells develop the ability to synthesize their own androgens. We hypothesize that a) androgens induce the in vitro expression and activity of cholesterol synthesis and esterification pathways and b) cholesterol synthesis, influx and efflux are altered in vivo to provide precursors for de novo androgen synthesis contributing to castration-resistant prostate cancer progression. METHODS: We have analyzed cholesterol metabolism in vitro (LNCaP, PC-3 and C4-2 cells in the presence of androgens) and in vivo (LNCaP xenograft model). The LNCaP xenograft model was used to mimic clinical progression of the disease. Tumors were excised from the same mouse at three stages: Androgen-Dependent (AD, prior to castration), Nadir (N, 8-days post castration) and Castration-Resistance (CRPC, 35-days post castration) and stored for further analysis. Protein expressions of AR, PSA and proteins involved in cholesterol synthesis and metabolism, influx and efflux as well as actin were determined by immunoblotting. Total cholesterol concentrations were determined within each excised tumor using a fluorescent assay and LC-MS. Tumoral steroid levels were assessed by LC-MS. RESULTS: Microsomal PC-3 and LNCaP cell HMG CoA reductase (cholesterol biosynthesis) activity was increased upon androgen treatment. ACAT1 activity (cholesterol esterification) was induced by androgens in PC-3 cells and this induction was AR- dependent as well as associated with increased ACAT1 protein expression. Tumor LDLr, SR-BI, HMG CoA reductase, ACAT1 and 2 as well as ABCA1 were altered during disease progression to CRPC likely to increase influx and synthesis of cholesterol. Total cholesterol levels increased in N and CRPC compared to AD. HMG CoA reductase expression was upregulated in N compared to AD (300%) and was maintained at this level at CRPC. Tumoral cholesterol biosynthesis ex vivo was increased from N to CRPC. Testosterone and dihydrosterone increased at CRPC to physiologically relevant levels and this may account for the increase in AR activation as determined by PSA expression at CRPC. CONCLUSIONS: Cellular cholesterol processes are altered by androgens and during progression to CRPC. Cholesterol from increased biosynthesis or uptake is likely a precursor for tumoral de novo androgen synthesis. ACKNOWLEDGEMENTS: Funding for this project was provided by the Canadian Institutes of Health Research (CIHR) and an NCIC-Terry Fox Group grant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5096.
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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".