Abstract 1994: Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells
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 rarely mutated nor suppressed. Par-4 is not only regulated at the expression level, but also post-translationally. Most recently, we reported the cisplatin-induced caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kd cleaved-Par-4 (cl-Par-4) fragment. In the present study, we investigated the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines. Briefly, we used cancer cell lines in which we produced stable clones expressing the cleaved form of PAR-4 (cl.PAR-4) using lentiviral particles. Using these models, we studied the regulation of cl.PAR-4 at the protein level using Western blots. Intriguingly, cl-Par-4 protein was weakly expressed in all stable clones despite constitutive transgene expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. We assessed the subcellular localization of cl-Par-4 in baseline and cisplatin-treated conditions using cytoplasmic/nuclear fractionation. Results showed that cl-Par-4 is localized in both the cytoplasm and nucleus compartments, but cisplatin treatment did not alter its localization. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure may in fact protect cl-Par-4 from proteasome-dependent degradation. To confirm proteasome involvement in this process, potential ubiquitination sites were predicted using bioinformatic tools. Interestingly, we showed that PI3K and MAPK pathways are also implicated in this post-translational regulation, as evidenced by an increase of cl-Par-4 in the presence of PI3K inhibitors (Wortmannin and NVP-BEZ235) and a decrease of cl-Par-4 using MAPK inhibitors (U0126 and PD98059). Finally using bioinformatics resources, we found diverse datasets showing similar results to those we observed with the proteasome and cl-Par-4. Indeed, we have showed, using data from a published study, that the use of Bortezomib (a potent proteasome inhibitor) significantly increased Par-4 expression in MCF7 cancer cells. These new findings add to the complex mechanisms regulating Par-4 expression and activity, and justify further studies addressing the biological significance of this phenomenon in gynecological cancer cells. Citation Format: Kevin Brasseur, Pascal Adam, Laurence Tardif, François Fabi, Sophie Parent, Éric Asselin. Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1994.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".