Abstract 86: Prolactin and testosterone induction of carboxypeptidase-D to promote cell survival is greater in prostate cancer cells than benign prostate cells, and their synergistic action in prostate cancer cells is effectively blocked by receptor antagonists Δ1-9-G129R and flutamide.
Bibliographic record
Abstract
Abstract Introduction: Carboxypeptidase-D (CPD), a membrane-bound metalloproteinase, cleaves C-terminal arginine, which is the substrate of nitric oxide synthase for production of nitric oxide (NO). NO regulates many cellular processes including tumor progression. We have reported that CPD and NO levels were upregulated by testosterone (T) or prolactin (PRL) to enhance survival of prostate cancer (pCa) cells. This study further characterized T/PRL regulation of CPD expression. CPD and NO levels in benign and malignant prostate cells/tissues were compared to determine their roles in pCa development. Methods: Quantitative RT-PCR (QPCR) was used to measure CPD mRNA levels in human prostate cell lines. Immunohistochemistry (IHC) and tissue microarray (TMA) analysis were used to compare CPD staining in prostate specimens. NO production was measured using 4,5-diaminofluorescein diacetate (DAF-2DA) assay. Results: QPCR analysis showed that CPD mRNA levels were not significantly altered in the benign prostate cell lines BPH-1 and RWPE1, as compared to a 3-4-fold increase in the pCa cell line LNCaP, following T or PRL treatment (P<0.01, n=3-6). T or PRL caused similar increases in other pCa cell lines (22Rv1, MDAPCa2b and PC-3), in which the androgen receptor (AR) and/or PRL receptor (PRLR) were expressed. DAF-2DA assays showed that NO levels were increased <1.6-fold in benign cells, compared to >3.5-fold in LNCaP cells after T/PRL stimulation. In LNCaP cells, T and PRL acted synergistically to upregulate NO, but were maximally suppressed when both receptors were inhibited with flutamide and Δ1-9-G129R in combination. Consistent with these results, TMA analysis showed significantly increased CPD staining from 8.9±3.8% (mean±SEM, n=18) of benign epithelial cell area to 30.9±2.9% (n=79) of tumor cell area (P<0.001). Endothelial cells in blood vessels associated with tumor were more likely to show positive staining than vessels of benign tissue (P<0.0001). A second TMA also showed increased CPD staining from 5.6±0.9% (n=48) in benign prostatic hyperplasia (BPH) to 17.9±2.1% (n=88) in pCa. TMA results were corroborated by IHC assessment of large (≥50mm2) prostate tissues from 35 men, where CPD staining increased from 13.1±2.9% in BPH to 29.5±4.4% in pCa. Conclusion: T/PRL-stimulated CPD mRNA levels were higher in tumor than in benign prostate cell lines. Likewise, CPD protein levels were higher in cancer than benign prostate specimens. Elevated CPD levels increased NO production, which was maximally suppressed when both the AR and PRLR were inhibited. Our results suggest that inhibition of both the AR and PRLR may be a more effective treatment for pCa and implicate the potential usefulness of the CPD-Arg-NO pathway as a therapeutic target for pCa. Citation Format: Catherine K. L. Too, Lynn N. Thomas, Jennifer Merrimen. Prolactin and testosterone induction of carboxypeptidase-D to promote cell survival is greater in prostate cancer cells than benign prostate cells, and their synergistic action in prostate cancer cells is effectively blocked by receptor antagonists Δ1-9-G129R and flutamide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 86. doi:10.1158/1538-7445.AM2013-86
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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 | 0.001 |
| 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) | 0.007 | 0.002 |
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".