Abstract 3347: Post-translational modifications of Akt isoform in chemoresistance of endometrial cancer
Bibliographic record
Abstract
Abstract Endometrial cancer is ranked fourth in importance among all types of cancer in women. This cancer is the most prevalent gynecological cancer. Akt is an inactive cytosolic serine/threonine kinase that plays a crucial role in cell fate by promoting cellular survival and proliferation. There are three Akt isoforms (1,2 and 3). This protein acts as a key regulator of numerous cellular phenotypes associated with cancer, such as cell proliferation, growth, metabolism, angiogenesis, malignant transformation and chemoresistance. It has been shown that Akt polyubiquitination is increased in cells treated with IGF-1. This ubiquitination is associated with an augmentation in the phosphorylation status of Akt. More and more evidence show that ubiquitination plays a pivotal role in kinase activation. In this study we observed ubiquitinated Akt (Ub-Akt) in the nucleus following IGF-1 treatment in the nucleus of endometrial cell lines (Ishikawa and KLE). We have established the ubiquitination pattern for the three Akt isoforms and their location in the cells. We also showed a cleaved fragment of Akt following cisplatin treatment in the same cell lines. Using western blot analyses, we observed a band at 60kDa corresponding to Akt and also other upper bands corresponding to Ub-Akt, in the nucleus of different endometrial cell lines. We have analyzed the pattern of two endometrial carcinoma (KLE and Ishikawa) and a cervical cancer cell line (HeLa). We found that both Akt1 and Akt3 were ubiquitinated in most of the cell lines. On the other hand, Akt2 was not ubiquitinated in any cell lines. We have used siRNA technology to knockdown each Akt isoform and characterized the loss of each isoform on the ubiquitination pattern for each cell line. We also treated cell lines with cisplatin to see which one of the three isoforms could be involved in chemoresistance and if Akt ubiquitination status could be involved in this process. We have separated fractions of the cytosol from the nucleus for each sample to investigate distribution of Ub-Akt isoforms in each cell line and confirmed the presence of Ub-Akt1 and -3 in the nucleus. We have also co-immunoprecipitated each Akt isoform and Ubiquitin to determine the exact ubiquitination pattern in cancer cells. KLE and Ishikawa had similarities in their pattern. Using immunoprecipitation, we observed that Akt1 was cleaved following cisplatin treatment. We observed that chemosentisitive cells had more cleaved Akt then chemoresistant lines. In conclusion, we are the first to establish a difference in the ubiquitination pattern for the different Akt isoform in the nucleus of endometrial cancer. We are also the first to show a cleavage of Akt isoforms linked to chemosensitive status of endometrial cancer. This study will form the basis for future investigations to determine the role of specific post-translationnal modifications of Akt isoforms in the endometrial cancer. Citation Format: Jérôme Grenier-Naud, Sophie Parent, Eric Asselin. Post-translational modifications of Akt isoform in chemoresistance of 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 3347. doi:10.1158/1538-7445.AM2014-3347
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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) | 0.002 | 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 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".