Abstract 2436: Regulation of breast cancer cell metabolism by the AMPK/ERR/PGC pathway
Bibliographic record
Abstract
Abstract Reprogramming of energy metabolism is now considered a hallmark of cancer. Deciphering molecular mechanisms underlying this process is therefore necessary to understand malignant transformation and cancer progression, but also to develop novel therapeutic tools. In the present study, our aim was to discover potential molecular links between two major pathways involved in energy metabolism in breast cancer cells: the energy sensor AMPK (AMP-activated protein kinase) in relationship with the estrogen-related receptors (ERRα and ERRγ) and their coactivators PGC-1α and PGC-1β (peroxisome-proliferator activated receptor γ coactivator-1). Using microarray analysis and qRT-PCR validation, we showed that activation of AMPK significantly altered the expression of the ERRs and the PGCs as well as their metabolic target genes. Moreover, pathway analysis revealed that a significant subset of genes regulated by AMPK pharmacological activation for 1 and 4 days were associated with the ERR/PGC transcriptional programs. Using metabolomics tools, we demonstrated that the energetic remodeling following AMPK pharmacological activation depends in part on ERR/PGC in breast cancer cells. Indeed, the induction in glucose and glutamine uptake and usage by activated AMPK was decreased by half following impairment of the ERR/PGC axis. Moreover, total, uncoupled and coupled respirations were also significantly decreased by ≈50% following ERR/PGC siRNA-mediated knock down. In order to understand the role of the ERRs in the transcriptional regulation of downstream targets of AMPK, we performed chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). Our results indicate that AMPK activation induces ERRs binding at the genomic scale, with the presence of 12,043 and 8,559 novel binding sites for ERRα and ERRγ, respectively. Basal, ERRs' binding to energy metabolism genes was already strong and did not change significantly after treatment. However, AMPK pharmacological activation induced ERRs binding to novel pathways such as numerous genes of the folate metabolism pathway. The biological consequence of the modulation of these pathways by the AMPK/ERR/PGC axis is presently under investigation. In conclusion, using transcriptomics, metabolomics and functional genomics, we revealed the interconnection of the AMPK with the ERR/PGC axis and the importance of this pathway in breast cancer cell metabolic states. Citation Format: Étienne Audet-Walsh, David Papadopoli, Julie St-Pierre, Vincent Giguère. Regulation of breast cancer cell metabolism by the AMPK/ERR/PGC pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2436. doi:10.1158/1538-7445.AM2014-2436
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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) | 0.003 | 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".