Abstract 5850: Salicylate sensitizes prostate cancer (PrCa) to radiotherapy; activation of AMPK and suppression of lipogenesis
Bibliographic record
Abstract
Abstract Radiotherapy (RT) is a key therapeutic modality for PrCa that achieves reasonable disease control rates in localized disease. However, this requires dose-escalated RT, which is associated with increased toxicity to surrounding tissues and leads to deterioration of patient quality of life. Improving the therapeutic ratio in PrCa RT is of high clinical importance. Aspirin has an established role in cancer prevention and studies suggested association with improved PrCa outcomes. It was shown that its metabolite salicylate (SAL) binds directly and activates the metabolic stress sensor AMP-activated kinase (AMPK). This is likely achieved through direct binding to the AMPK β1 subunit, leading to enhanced AMPK activity through suppression of AMPK α-subunit T172 de-phosphorylation. In this study we examined the ability of SAL to sensitize PrCa to RT. Hormone insensitive (PC3) and sensitive (LnCap) human PrCa cells, as well as PC3 xenografts grown in immunocompromised nude mice were subjected to SAL and RT treatments. SAL mediated a dose-dependent inhibition of proliferation and clonogenic survival in both PrCa cell lines and suppressed de novo lipogenesis (DNL). This was detected at μM concentrations of the drug, which can be safely achieved in human circulation. SAL (100-500 μM) radio-sensitized PC3 and LnCap cells, and enhanced the ability of SAL to inhibit DNL. In animals treated with conformal RT (10Gy) to the tumor xenografts, Salsalate feeding (chow diet containing 2.5gr/kg) enhanced the cytotoxicity of RT detected as reduced tumor growth kinetics and weight and volume at sacrifice. Salicylate treatment of cells or salsalate feeding of mice led to increased AMPK activity in cells and tumors, inhibitory phosphorylation of Acetyl-CoA Carboxylase and reduction of AktThr308 phosphorylation. These results indicate that SAL could improve radiation response in PrCa through a mechanism involving the suppression of DNL. This is achieved at clinically attainable doses of SAL. This work supports prospective investigation of SAL as a radio-sensitizer in early phase clinical trials of localized PrCa. Note: This abstract was not presented at the meeting. Citation Format: Theodoros Tsakiridis, Katarina Marcinko, Linsday Broadfield, Linda Villani, Carrie Gerdes, Danitra Maharaj, Tom Farell, James Wright, Gregory Steinberg. Salicylate sensitizes prostate cancer (PrCa) to radiotherapy; activation of AMPK and suppression of lipogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5850. doi:10.1158/1538-7445.AM2017-5850
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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) | 0.006 | 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".