The affect of androgens on fatty acid oxidation in prostate cancer cells
Bibliographic record
Abstract
474 Epidemiological evidence suggests that dietary fat plays a role in the etiology of prostate cancer (PC). Oxidation of fatty acids (FA) results in the generation of reactive oxygen species (ROS), which have been postulated to play a key role in the initiation and progression of PC. The purpose of this study was to determine whether androgens, which stimulate the growth of PC, also play a role in fatty acid (FA) uptake and degradation and consequently increase mitochondrial ROS production. The model used compares the effect of a synthetic androgen (R1881) and an androgen receptor (AR) blocker (bicalutamide) on androgen responsive 22rv1 prostate cancer cells. Methods used were quantitative PCR, 14C-labeled long chain FA degradation assay and western blot analysis. We found that androgen supplementation increased the mRNA expression of the rate limiting enzyme in the fatty acid degradation Carnitine Palmitoyltransferase I (CPT1), in both liver and muscle isoforms and bicalutamide inhibited this phenomenon. Consequently, androgen supplementation increased the oxidation of long chain FA and this was reversed by bicalutamide. In addition, R1881 decreased the expression of Acetyl CoA Carboxylase (ACC) and its inactivated form phospho-ACC, an enzyme responsible for regulating the synthesis of the CPT1 inhibitor, malonyl-CoA. Subsequently we demonstrated that blockage of mitochondrial ROS generation by 2 different inhibitors- rotenone and thenoyltrifluoroacetone could eliminate the androgen induced generation of cellular ROS which is coupled to FA oxidation, bringing it to the same levels of PC cells that were deprived of androgens or treated with bicalutamide. Thus, we propose that the increase in ROS levels in PC cells is androgen regulated through the increased expression of CPT1 and decreased expression of ACC. Therefore, the FA that is taken up into PC cells is available for mitochondrial oxidation, a process that is also positively regulated by androgens, leading to the increased production of ROS that are associated with cancer cell proliferation and mutagenesis. In addition, the observed change in CPT1 and ACC expression may present a future target in reducing ROS levels for the purpose of PC prevention and therapy. Furthermore, dietary restrictions or anti-oxidants, also each have different inhibitory but complementary effects on the proposed mechanism.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".