Abstract 1800: Inhibition of scavenger receptor class B type I suppresses androgen pathway activity and induces cytotoxic stress in C4-2 castration resistant prostate cancer cells
Bibliographic record
Abstract
Abstract Existing therapies for castration-resistant prostate cancer (CRPC) extend life and provide clinical benefit; however, patients continue to develop therapeutic resistance. Androgen pathway activity persists in CRPC even under maximal androgen blockade conditions. A proposed mechanism for continued androgen pathway signaling is de novo intratumoral synthesis of androgen receptor agonists from the precursor cholesterol. The high density lipoprotein(HDL)-cholesterol receptor, scavenger receptor class B type I (SR-BI), is upregulated in CRPC models in vitro and in vivo. Here, we test the hypothesis that SR-BI is a source of cholesterol for de novo steroidogenesis in CRPC cells using the castration-resistant LNCaP-derived cell line, C4-2. Cells were transfected with either non-targeted (NC) or stealth RNAi duplexes (Thermo Fisher) targeting SR-BI to silence protein expression (SR-B1 KD). Prostate specific antigen (PSA) levels in media from SR-B1 KD samples were reduced to 39% of that seen in control cell media (20.9 ± 1.4 ng/mL/μg protein SRBI-KD vs. 34.5 ± 2.4 ng/mL/μg protein NC; n = 4, p < 0.05). Intracellular testosterone concentrations measured by LC-MS showed a 2-fold reduction in SRBI-KD samples (0.20 ng/mL/mg) compared to NC (0.41 ng/mL/mg; n = 1). Additionally, SR-BI KD cells exhibited reduced cell viability as measured by MTS assay and induction of G1/S cell cycle arrest as assessed by propidium iodide staining cell cycle analysis by flow cytometry (70.9 ± 7.9% G0-G1 phase fraction SRBI-KD vs. 58.3 ± 4.1% NC; n = 4, p < 0.05). SR-BI KD cells exhibited evidence of increased cell stress relative to NC cells. SR-BI-KD cells showed elevated induction of autophagy as assessed by measuring changes in LC3-I:LC3-II ratio by immunoblotting and formation of autophagosomes by immunofluorescence, alongside induction of senescence as assessed by measuring senescence associated beta-galactosidase (SA-β-gal) activity using flow cytometry analysis and a fluorogenic substrate. Further, treating C4-2 cells with an established SR-B1 inhibitor, BLT-1, lead to decrease PSA secretion, and co-treatment with the common cholesterol synthesis inhibitor, simvastatin, synergistically decreased PSA secretion from C4-2 cells. These results suggest that under androgen-deprived conditions, SR-BI targeting can decrease androgen pathway signalling and induce cellular stress, leading to G1/S arrest and decreased proliferation in the absence of an apoptotic induction. Lastly, combined inhibition of cholesterol uptake (BLT-1) and synthesis (Simvastatin) lead to a synergistic decrease in PSA secretion indicating the possibility that a multi-faceted cholesterol blockade approach to CRPC treatment may improve response to maximal hormone blockade by disrupting intratumoral steroid production. Citation Format: Jacob A. Gordon, Ankur Midha, Mitali Pandey, Kishor Wasan, Michael E. Cox. Inhibition of scavenger receptor class B type I suppresses androgen pathway activity and induces cytotoxic stress in C4-2 castration resistant prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1800.
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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".