A ligand-independent androgen receptor function protects from inositol hexakisphosphate-induced cell death
Bibliographic record
Abstract
14566 Background: The androgen receptor (AR) is often aberrantly expressed or activated in hormone-refractory (HR) prostate cancer (PCa). Though it is not clear whether this is directly linked to AR expression, various cell survival pathways are over-activated in HR-PCa, which is characterized by its poor clinical outcome and resistance to available therapies. Inositol hexakisphosphate (IP6) is a phytochemical anti-cancer agent, which we have found to be more effective in PCa cell lines that do not express the AR. Our goal was to address the mechanism of IP6-induced cell death and to evaluate if and how the AR may interfere with its activity. Methods: We used LNCaP, DU145, 22Rv1 as well as wild-type PC3 and AR-expressing PC3 (PC3AR) cell lines to assess the metabolic toxicity of IP6 by WST-1 assay in normal, androgen-supplemented, and androgen-depleted cell culture conditions. A siRNA targeting the androgen receptor (AR) was used to control for genuine AR-mediated effects in the PC3/PC3AR cell lines. Apoptosis was quantified using fluorogenic caspase-3 assays as well as quantitative DNA fragmentation assays. Expression of a variety of genes involved in apoptosis and cell survival pathways was evaluated by real time PCR. Results: While the activity of IP6 was not modulated by the presence of androgens for any cell line, PC3AR cells were significantly more resistant to IP6 than wild-type PC3 cells according to WST-1, caspase-3 and DNA fragmentation assays (p < 0.05). Down-regulation of the AR in the PC3AR cell line resulted in increased metabolic toxicity of IP6 on these cells (p < 10 −5 ). Although treatment with IP6 resulted in the up-regulation of the pro-apoptotic genes Puma, Noxa, as well as of IRF-2 and IkB-αλπηα in PC3 cells, this did not occur in PC3AR cells (p < 0.05). Conclusion: We conclude that, at least in PC3/PC3AR, cells IP6 sensitivity is linked to a ligand-independent function of the AR. To our knowledge, this is the first report of a ligand-independent AR function involved in resistance to a cytotoxic compound. Establishing the molecular details of this novel function is a major part of our ongoing research. No significant financial relationships to disclose.
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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) | 0.001 | 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) | 0.000 | 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".