Abstract 824: Regulation of PAR-4 activity in chemoresistant ovarian cancer cells: A major role for the cleaved fragment in the control of apoptosis.
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 we have shown that it has all the necessary sites to induce apoptosis. In the present study, we have investigated the mechanisms regulating PAR-4 and its cleaved form in chemosensitive versus chemoresistant ovarian cancer cells. Using A2780/A2780CP ovarian cell lines (sensitive and resistant to cisplatin in vitro) and OV2295/OV2295-2 (sensitive cells obtained before treatment and cisplatin resistance acquired in vivo), we compared expression level of PAR-4 and its cleaved form (cl.PAR-4) after treatment with cisplatin. Only sensitive cancer cells have a decrease of PAR-4 level and an increase of cl.PAR-4. To further investigate mechanisms behind cl.PAR-4, we produced stable clones of A2780/A2780CP expressing cl.PAR-4-MYC using lentiviral particles. Our first observations were that, upon cisplatin treatment, cl.PAR-4-MYC protein level was increased indicating post-translational mechanisms regulating cl.PAR-4. Using proteasome inhibitor, MG-132, cl.PAR-4-MYC expression level highly increase indicating a link between cl.PAR-4 and the proteasome. We also obtained preliminary results indicating a regulation of cl.PAR-4-MYC by the MAPK pathway. Using U0126, a MEK ½ inhibitor, we were able to lower cl.PAR-4-MYC protein level and also basal cl.PAR-4. Upon cisplatin treatment in A2780-cl.PAR-4, p-ERK ½ expression increased in correlation with the increase of cl.PAR-4-MYC while in A2780-Empty cells, the level of p-ERK ½ was not influenced. We also investigated the localization of cl.PAR-4 using cytoplasmic/nuclear fractionation and harvested the culture supernatant to verify if the protein is excreted from the cancer cells. The fractionation indicates that cl.PAR-4-MYC is localized equally in both nucleus and cytoplasm. We have analyzed the supernatant and found that cl.PAR-4 is also present outside of the cell indicating an excretion/secretion mechanism of cl.PAR-4. Further analyses of the post-translational mechanisms behind cl.PAR-4 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 ovarian cancer cells. These findings may open new treatment options against women's cancers by improving their health. Citation Format: Kevin Brasseur, Sophie Parent, Éric Asselin. Regulation of PAR-4 activity in chemoresistant ovarian cancer cells: A major role for the cleaved fragment in the control of apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 824. doi:10.1158/1538-7445.AM2013-824
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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 | 0.000 |
| 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) | 0.000 | 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".