17-allylamino-17-demethoxygeldanamycin disrupts SYT-SSX-β-catenin interaction in synovial sarcoma
Bibliographic record
Abstract
B32 The Hsp90 chaperone inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is effective against synovial sarcoma (SS) in vitro ; this study tested if its mechanism of action involves destabilization of the disease-defining fusion oncoprotein SYT-SSX and its interaction with β-catenin. SS has a poor prognosis overall as it typically exhibits little response to conventional chemotherapy; drugs that specifically target the aberrations that underlie SS pathogenesis are likely to be more effective. Although its role in pathogenesis is incompletely understood, SYT-SSX is an attractive therapeutic target because it is ubiquitous in SS, its expression in non-malignant cell lines has been shown to be oncogenic, and β-catenin-SYT-SSX interaction in the nucleus increases nuclear β-catenin levels and enhances β-catenin-mediated transcription, demonstrating a link between SYT-SSX and the cell cycle machinery. Accordingly, relatively high levels of nuclear-localized β-catenin can be demonstrated in a significant proportion of SS cases; this likely plays a role in SS pathogenesis and methods to disrupt the SYT-SSX-β-catenin interaction may lead to the development of effective clinical therapies. 17-AAG destabilizes fusion oncoproteins in other cancers, suggesting it may also destabilize SYT-SSX, and by extension result in decreased nuclear β-catenin and β-catenin-mediated signaling. To examine this possibility, the effects of 17-AAG on the subcellular localization of β-catenin, total cellular levels of SYT-SSX and β-catenin and levels of β-catenin-mediated transcription from both exogenous and endogenous sources were examined in two SS cell line models, SYO-1 and Fuji. This study found that 17-AAG disrupts the interaction between β-catenin and SYT-SSX, promotes redistribution of β-catenin from the nucleus to the cell membrane and decreases levels of β-catenin-mediated transcription in both cell line models. These effects were not associated with degradation of SYT-SSX itself, however, suggesting that 17-AAG inhibits formation of the β-catenin-SYT-SSX complex by destabilizing unidentified intermediary binding partner(s), or by affecting post-translational modification(s) of β-catenin or SYT-SSX required for interaction. This study demonstrates that the clinically-applicable drug 17-AAG disrupts a connection between the SS-defining fusion protein SYT-SSX and the cell cycle machinery and presents additional evidence for SYT-SSX and β-catenin as valid therapeutic targets in SS.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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".