Abstract 5561: 20(S)-Protopanaxadiol-aglycone downregulates full-length and ligand-independent splice variants of androgen receptor
Bibliographic record
Abstract
Abstract Prostate carcinogenesis is characterized by a long latency of 20 to 40 years. Chemoprevention to manage the disease at an early stage to prevent it from becoming clinical relevant is increasingly being recognized as an important aspect of prostate cancer control. Androgen signaling plays a vital role in the development and progression of prostate cancer. Finasteride and dutasteride, which inhibit the formation of dihydrotestosterone, are the only chemopreventive agents that have been shown definitively to decrease prostate cancer incidence. However, their effectiveness appears to be limited to Gleason 6 cancers. In addition, cancer cells expressing high level of constitutively-active, ligand-independent splice variants of androgen receptor may not be responsive to treatment with finasteride or dutasteride. Therefore, there is an urgent need to develop new chemopreventive agents that could block androgen signaling through both the full-length and splice variants of androgen receptor. Ginsenosides are the main ingredients responsible for the pharmaceutical functions of ginseng, a commonly used medicinal herb among cancer patients. Several ginsenosides have been implicated to inhibit prostate cancer cell growth. However, the underlying mechanism is largely unknown. Here we provide the first evidence that, in prostate cancer cells, ginsenoside 20(S)-protopanaxadiol-aglycone (PPD) effectively downregulates the expression and activity of androgen receptor, including both the full-length and the constitutively-active, ligand-independent splice variants. The effect of PPD on androgen receptor is manifested by an immediate drop in protein, followed by a reduction in mRNA. The initial decrease in androgen receptor protein could be attributed to PPD induction of proteasome-mediated degradation, possibly as a result of disrupted androgen receptor N-C interaction. Depressing the inhibitory effect of PPD on androgen receptor by knocking down androgen receptor before PPD treatment weakens significantly the growth-suppressive activity of PPD, indicating the important contribution of androgen receptor downregulation to PPD action in prostate cancer cells. This report is also the first to establish the in vivo preclinical efficacy of PPD against the growth of androgen receptor-expressing prostate cancer cells, which constitute the majority of clinical prostate carcinomas. In addition to tumor growth inhibition, PPD supplementation also leads to in vivo downregulation of androgen receptor and its target gene, prostate-specific antigen. Considering the critical role of androgen receptor signaling in prostate cancer development and progression and the role of the ligand-independent androgen receptor splice variants in disease recurrence, our findings provide strong justification for further development of PPD for prostate cancer prevention and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5561. doi:10.1158/1538-7445.AM2011-5561
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".