Abstract A010: Proteasome inhibitors induce a BAX and BAK independent, non-canonical apoptosis
Bibliographic record
Abstract
Abstract In the intrinsic pathway of apoptosis, death stimuli (including drugs, cellular stress, viral infections, etc.) trigger the oligomerization of BAX and BAK resulting in pore formation in the outer mitochondrial membrane to release cytochrome c from the intermembrane space. The released cytochrome c then activates APAF-1 and CASPASE9 to form a 1.4 MDa complex known as apoptosome, which recruits and activates downstream caspases that dismantle the cell. However, we have found that proteasome inhibition leads to a BAX and BAK independent apoptotic cell death. We show using immunofluorescence, fluorogenic assays, and flow cytometry that the proteasome inhibitors, bortezomib and MG-132, trigger a caspase dependent cell death that requires the apoptosome components APAF-1 and CASPASE9, but not cytochrome c. Furthermore, size exclusion chromatography revealed that unlike classical death stimuli, which induce the mega-dalton canonical apoptosome fomation, proteasome inhibitors induce a minor shift in APAF-1, forming a smaller, non-canonical apoptosome. Current efforts are focused on the identification of the APAF-1 activator. Our results indicate the existence of a non-canonical caspase-dependent cell death pathway, which could be a novel therapeutic target in malignancies by bypassing the BCL-2 family of apoptotic regulators. Citation Format: Tresor O Mukiza, Ricardo Enrique-Rodriguez, Amit Budhraja, Lauren Brakefield, Tudor Moldoveanu, Joseph T Opferman. Proteasome inhibitors induce a BAX and BAK independent, non-canonical apoptosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A010.
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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) | 0.013 | 0.002 |
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".