Abstract 6770: TFEB-dependent signals confer resistance against chemotherapeutic drug-induced nucleolar stress
Bibliographic record
Abstract
Abstract In addition to their main role in inhibiting cell growth, chemotherapeutic agents are also known to trigger protective signals that equip cancer cells with resistance mechanisms. Notably, treatment with chemotherapeutics has been associated with increased lysosome-related functions, such as autophagy, which protect cells from death. Our previous research showed that gemcitabine enhances autophagy and lysosomal function, particularly in HeLa and pancreatic cancer cells. However, the precise mechanisms through which this nucleoside analog elicits a protective autophagic response are still elusive. While gemcitabine is designed to interfere with DNA replication, it has also been noted to cause nucleolar stress. In our current study, we sought to determine if gemcitabine induces nucleolar stress and, if so, to examine whether this stress mimics the effects of gemcitabine by triggering a cytoprotective response. Our findings show that: 1) Gemcitabine induces nucleolar stress, indicated by the nucleoplasmic localization of nucleolin and nucleolar morphological changes. 2) Treatment of cells with the nucleolar stress inducer CX5461 leads to an autophagy and lysosomal response, monitored by increased LC3 and LAMP1 puncta, along with elevated levels of mature cathepsin B. 3) Additionally, CX5461-treated cells show an enriched nuclear localization of TFEB, the master regulator of autophagy and lysosomal function, detected by immunofluorescence and subcellular fractionation. The nuclear enrichment of TFEB correlates with the enrichment of faster migrating forms of TFEB (indicative of post-translational modification changes), as detected by immunoblotting. 4) Like gemcitabine, CX5461 impairs cell growth. 5) Nonetheless, clonogenic assays indicate that cells with reduced TFEB function (shTFEB) are more sensitive to CX5461 than control cells. 6) In parallel, shTFEB cells exhibit higher levels of apoptotic markers in response to CX5461 treatment, suggesting that TFEB confers resistance to nucleolar stress. Overall, our data provide the first evidence that nucleolar stress triggers a TFEB-dependent protective response. Conducted in cells without functional wild-type p53 signaling, our findings suggest that TFEB could act as a sensor of nucleolar stress, relaying a protective response and helping cells engage in timely and coordinated actions to cope with stress. Therefore, our results support the involvement of TFEB in chemoresistance. These TFEB-protective signals may be particularly relevant to cancers with high TFEB expression levels, such as pancreatic cancer. Citation Format: Marjorie Rolland, Florence McDuff, Laure Bessy, Benoit Marchand, Marie-Josee Boucher. TFEB-dependent signals confer resistance against chemotherapeutic drug-induced nucleolar stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6770.
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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) | 0.004 | 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".