Abstract 1583: Inhibition of proline isomerase Pin1 interrupts the function of the androgen receptor N-terminal domain and suppresses androgen-independent growth of prostate cancer cells
Bibliographic record
Abstract
Abstract Patients with advanced prostate cancer continue to develop lethal castration-resistant prostate cancer (CRPC) despite hormone therapy and maintaining castrate levels of serum androgen. Most CRPC appears to be dependent on the androgen receptor (AR), but instead of the C-terminal ligand-binding domain, it is the N-terminal domain (NTD) harboring a powerful transactivation domain that drives AR transcriptional activity. This was supported by the discovery of AR splice variants (ARv567es and V7) which are constitutively active, do not encode a functional ligand-binding domain, and correlate with poor patient outcome. The AR NTD is intrinsically disordered, but it contains several putative binding sites for Pin1, a proline isomerase specific for phosphorylated-Ser/Thr-Pro motifs. Since the innate ability of the AR NTD to adopt multiple transient structures is important for transactivation of AR, we aimed to determine whether Pin1 regulates motifs within the AR NTD. We tested several known inhibitors of Pin1 in cell-based assays that measure proliferation or transcription mediated by AR. Our results demonstrated that inhibition of Pin1 interrupted the function of the AR NTD. The Pin1 inhibitor juglone effectively and specifically blocked transcription mediated by AR induced by androgen, as well as transactivation of the AR NTD in the presence of IL-6. We found that Pin1 predominantly interacted with a specific region of the AR NTD containing two Pin1 binding sites, and by inhibiting Pin1 the interactions between endogenous AR and STAT3 became attenuated. Furthermore, Pin1 inhibitors were more effective than second-generation anti-androgens in blocking androgen-independent proliferation of LNCaP95 cells driven by AR variants. Here we describe that Pin1 is a critical factor for transcription mediated by AR, regardless of ligand, by regulating the AR NTD. Understanding the molecular mechanisms that may promote AR signaling in the absence of androgen will aid the development of more effective therapies for CRPC. Citation Format: Jacky K. Leung, Yusuke Imamura, Minoru Kato, Nasrin R. Mawji, Marianne D. Sadar. Inhibition of proline isomerase Pin1 interrupts the function of the androgen receptor N-terminal domain and suppresses androgen-independent growth of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1583. doi:10.1158/1538-7445.AM2017-1583
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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 | 0.001 |
| 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".