Abstract 4119: High-throughput proteomics reveals that enzymes of the ketogenic pathway are upregulated during prostate cancer progression
Bibliographic record
Abstract
Abstract Prostate cancer is the most common malignancy and the second leading cause of cancer related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumours that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line, and its androgen independent derivative, LNCaP-SF. By using stable isotope labelling with amino acids in cell culture (SILAC) coupled to mass spectrometry, we assessed the differential global protein expression between the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins, in total. Bioinformatic prioritization resulted in 42 up-regulated and 46 down-regulated proteins in LNCaP-SF cells, compared to LNCaP cells. Our top candidate was HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells. This was further verified using western blotting, indicating the importance of this pathway during the progression of prostate cancer to androgen-independence. To determine whether these enzymes are up-regulated in clinical samples, we performed qPCR analysis on human prostate cancer tissues, from which we observed significantly increased transcript levels of HMGCS2 (p<0.05), OXCT1 (P<0.05), ACAT1 (p<0.001), and BDH1 (p<0.001). In addition, the protein expression of all five ketogenic pathway enzymes was elevated in high grade prostate cancer (Gleason Grade >8) based on immunohistochemistry analysis. ACAT1 displayed the most prominent protein expression patterns, as it exhibited very minimal staining in normal samples, moderate levels in low grade cancer, and high expression during high grade disease. Further assessment of ACAT1 expression demonstrated significantly greater ACAT1 expression in bone metastatic lesions (P<0.001). Altogether, our results indicate that enzymes belonging to the ketogenic pathway become up-regulated during high grade prostate cancer, and could serve as potential biomarkers for diagnosis of high grade disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4119. doi:1538-7445.AM2012-4119
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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 | 0.000 |
| 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".