Implications of PI3K/AKT inhibition on REST protein stability and neuroendocrine phenotype acquisition in prostate cancer cells
Bibliographic record
Abstract
// Ruiqui Chen 1 , Yinan Li 1 , Ralph Buttyan 1 and Xuesen Dong 1 1 Vancouver Prostate Center, Department of Urologic Sciences, The University of British Columbia, Vancouver, Canada Correspondence to: Xuesen Dong, email: // Keywords : PI3K/AKT inhibition, REST degradation, neuroendocrine differentiation, neuroendocrine prostate cancer Received : July 02, 2017 Accepted : July 06, 2017 Published : July 19, 2017 Abstract Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that arises as a consequence of rigorous androgen receptor (AR) pathway inhibition (ARPI) therapies. While the PI3K/AKT pathway has been investigated as a co-therapeutic target with ARPI for advanced PCa, whether this strategy can prevent tumor progression to t-NEPC remains unknown. Here, we report that PI3K/AKT inhibition alone reduces RE-1 silencing transcription factor (REST) protein expression and induces multiple NE markers in PCa cells. The loss of REST by PI3K/AKT inhibition is through protein degradation mediated by the E3-ubiquitin ligase β-TRCP and REST phosphorylations at the S1024, S1027, and S1030 sites. Since AR inhibition can also deplete REST, the combinational inhibition of PI3K/AKT and AR further aggravated REST protein reduction. We profiled the transcriptomes of AKT and AR inhibitions in the LNCaP cells. The Gene Set Enrichment Analysis (GSEA) showed that these transcriptomes are highly correlated with the REST-regulated gene signature. Co-targeting AKT and AR resulted in a higher correlation comparing to those of single treatment. Comparing these transcriptomes to the t-NEPC gene signature in patients by GSEA, we observed that adding AKT inhibition to AR blockade enhanced the expression of neurogenesis-related genes and resulted in a stronger and broader upregulation of REST-regulated genes specific to t-NEPC. These results indicate that AKT pathway inhibition can induce neuroendocrine differentiation of PCa cells via REST protein degradation. It delineates a potential risk for the AR and PI3K/AKT co-targeting strategy as it may further facilitate t-NEPC development.
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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) | 0.001 | 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 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".