Phosphorylation of Akt isoforms induces resistance to cisplatin, doxorubicin and paclitaxel in human uterine cancer cells
Bibliographic record
Abstract
5943 Endometrial cancer is the leading type of gynecological cancer and is the fourth in importance among all type of cancer in women. While most patients with disease recurrence after primary therapy are incurable, there is a subset of patients treated with surgery only who have recurrence confined to the pelvis that may be cured with appropriate radical pelvic irradiation. However, a major difficulty in chemotherapy is cellular resistance to chemotherapeutic drugs and the mechanisms involved remain to be elucidated. Serine/threonine protein kinase Akt activity has been shown to suppress apoptosis in cancer cells. To date, three isoforms of Akt have been identified: Akt1, Akt2, Akt3. Akt isoforms are expressed and regulated differently in normal and cancer cells but their specific roles remain to be clarified. Objective of this study was to investigate the possible involvement of Akt activity in the resistance of human endometrial cancer cells to cisplatin, doxorubicin and paclitaxel. In the present study, one endometrial (KLE), one cervical (Hela) cancer cell lines known as wild-type PTEN (tumor suppressor phosphatase tensin homologue, a lipid phosphatase involved in the regulation of Akt phosphorylation) and one mutated-PTEN (Ishikawa) were used. Basal levels of Akt1, Akt2, Akt3 and PTEN mRNAs were determined by real time quantitative RT-PCR and Western blot analyses were carried out to determine protein abundance. Akt1 mRNA and protein were present in all cell lines studied. Akt2 and Akt3 mRNAs and proteins were strongly expressed in KLE cells. Surprisingly, Akt phosphorylation was found in KLE cells. Cisplatin, doxorubicin and paclitaxel induced cell death in Ishikawa and Hela cells but KLE cells expressing Akt2 and Akt3 remained resistant to these chemotherapeutic agents. We have found that overexpression of Akt using a constitutively active expression vector resulted in an up-regulation of cIAP-1 expression, an inhibitor of caspase activity. Moreover, transfection of constitutively active Akt vector reduced cisplatin sensitivity whereas Akt1, Akt2 and Akt3 knockdown by siRNA had the opposite effect and amplified the action of cisplatin on cell death induction. These findings suggest that Akt, particularly Akt2 and Akt3, may be involved in chemoresistance to cisplatin, doxorubicin and paclitaxel and that cIAP-1, or other member of IAP family, may be involved in the process of chemoresistance in uterine cancers. Supported by CIHR (MOP-66987).
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Bench or experimental | high |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Bench or experimental | high |
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) | 0.001 | 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, unvalidatedLabeled directly by 2 models reading the full record.
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".