Abstract 1256: Protein kinase G type Iα activity in human ovarian cancer cells contributes to enhanced Src activation and DNA synthesis/cell proliferation
Bibliographic record
Abstract
Abstract We have previously shown that basal activity of the nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG) signaling pathway protects human ovarian cancer cells against spontaneous apoptosis and confers resistance to cisplatin-induced apoptosis. The present study determines whether basal PKG activity up-regulates Src and induces cell proliferation in human ovarian cancer cells. PKG-Iα was identified as the predominant isoform of PKG expressed in both cisplatin-sensitive OV2008 and cisplatin-resistant A2780cp human ovarian cancer cells. In both cell lines, both ODQ, an inhibitor of endogenous-NO-induced cGMP biosynthesis, and DT-2, highly-specific inhibitor of PKG-Iα activity, as well as PKG siRNA caused concentration-dependent inhibition of DNA synthesis (assessed by BrdU incorporation) under normal (plus-serum) growing conditions, indicating an important role of basal cGMP/PKG-Iα activity in promoting cell proliferation. DNA synthesis in OV2008 cells was dependent on Src activation, determined using selective Src inhibitor, 4-(4′-phenoxyanilino)-6,7-dimethoxyquinazoline (SKI-1). In vitro co-incubation of human recombinant Src and PKG-Iα resulted in Src-mediated tyrosine-phosphorylation of PKG-Iα and enhanced Src autophosphorylation at tyrosine-416, suggesting that Src directly tyrosine-phosphorylates PKG-Iα and the interaction between PKG-Iα and Src also leads to enhanced Src activation. The result was further confirmed by using immunoprecipitation of PKG, showing a concentration-dependent decrease in PKG tyrosine-phosphorylation by SKI in both ovarian cancer cell lines. In intact OV2008 cells, inhibition of basal PKG-Iα activity with DT-2 dramatically reduced endogenous Src activation and completely blocked the elevation of DNA synthesis stimulated by EGF. The data suggest that Src activation and DNA synthesis/cell proliferation in human ovarian cancer cells are dependent on endogenous basal PKG-Iα activity. The NO/cGMP/PKG-Iα signaling pathway may provide a novel therapeutic target for disrupting the proliferation of ovarian cancer cells. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1256.
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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) | 0.003 | 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".