Abstract 3386: Post-translational mechanisms related to PAR-4 regulation in endometrial cancer
Bibliographic record
Abstract
Abstract Prostate Apoptosis Response-4 (PAR-4) is a tumor suppressor protein whose expression level in cancer is frequently decreased; however it is neither mutated nor suppressed. A unique feature of PAR-4 is that it can induce apoptosis selectively in cancer cells without destroying normal cells, giving it an interest in anti-cancer targeted therapy. PAR-4 is not only regulated at the expression level, but also post-translationally by phosphorylation and protein cleavage. Most recently, the caspase-3 cleaved form of PAR-4 has been demonstrated by our laboratory and this fragment might be responsible for PAR-4 apoptosis mechanism. In the present study, we have investigated the mechanisms regulating PAR-4 and its cleaved form in endometrial cancer cell lines. Using endometrial cisplatin-sensitive cell line (Ishikawa) and endometrial cisplatin-resistant cell lines (HEC-1A), we compared expression level of PAR-4 and its cleaved form (cl.PAR-4) after treatment with cisplatin. PAR-4 level was decreased more in sensitive cancer cells and cl.PAR-4 was then increased indicating a possible link with chemoresistance. To further investigate mechanisms by which cl.PAR-4 is linked to apoptosis, we produced stable Ishikawa and HEC-1A cells clones expressing cl.PAR-4-MYC using lentiviral particles. Our first observations were that, upon cisplatin treatment, cl.PAR-4-MYC protein level was increased while cDNA level was stable indicating post-translational mechanisms regulating cl.PAR-4. Using proteasome inhibitors, MG-132 and lactacystin, cl.PAR-4-MYC expression level increased indicating a link between cl.PAR-4 and the proteasome. We also investigated the role of AKT in relation with cl.PAR-4 using the PI3K inhibitor Wortmannin. Results indicated that pAKT negatively regulate cl.PAR-4-MYC dose-dependently. We also found out that phospho-PAR-4 Thr163 is highly expressed in mutated-PTEN endometrial cancer cell line Ishikawa and RL95-2 which are expressing high level of phospho-AKT. We investigated the localization of PAR-4 and cl.PAR-4 using cytoplasmic/nuclear fractionation and the results indicates that cl.PAR-4-MYC and endogenous PAR-4 are localized in both nucleus and cytoplasm while endogenous cl.PAR-4 is mainly cytosolic. This localization of cl.PAR-4 may have a role in its ability to induce apoptosis like full length PAR-4. Finally, bioinformatic analyses have been done to suggest potential ubiquitination sites and phosphorylation sites responsible for the regulation of cleaved PAR-4. Further analyses of the post-translational mechanisms involved in cl.PAR-4 activity still need to be investigated to better understand the regulation of this potential tumor suppressor. By better understanding the mechanisms of PAR-4 and its cleaved form, we may be able to utilize this protein to sensitize chemoresistant endometrial cancer cells to chemotherapy. These findings may open new treatment options against endometrial cancers. Citation Format: Kevin Brasseur, Sophie Parent, François Fabi, Éric Asselin. Post-translational mechanisms related to PAR-4 regulation in endometrial cancer. [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 3386. doi:10.1158/1538-7445.AM2014-3386
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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 teacher head, 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".