Abstract A09: Downregulation of PI3K signaling by high ERK activity prevents transformation by oncogenic RAS
Bibliographic record
Abstract
Abstract In this study, we investigated the contribution of strong ERK signals to tumor suppression. Oncogenic forms of RAS are found in up to 30% of all human cancers and are established drivers of tumor initiation and maintenance. However, strong expression of these oncogenes in normal cells induces cellular senescence, a putative tumor-suppressive barrier. RAS activates several signaling pathways, such as the PI3K/AKT pathway, the RAL pathway and the classical RAF/MEK/ERK MAP Kinase pathway. We previously found that RASV12-induced senescence of primary cells is prevented by attenuation of ERK signaling. Mechanistically, strong ERK signaling promotes senescence by inducing selective proteasome-dependent protein degradation. This “Senescence-Associated Protein Degradation” (SAPD) targets proteins required for cell cycle progression, mitochondrial functions, cell migration and cell signaling. Here we show that in addition to abrogating RAS-induced senescence, low ERK activity allows transformation of primary human cells stably expressing RasV12 and hTERT as well as transformation of RasV12-expressing rodent cells. Furthermore, in a Kras-driven mouse model of multistage pancreatic progression, decreased p-ERK levels correlate with tumor initiation. Taken together, these observations suggest that overactivated ERK may serve as a barrier for oncogenic transformation of cells acquiring activating RAS mutations. We found that the antitumor effects of aberrant ERK signaling include the inhibition of the phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling pathway. Consequently, transformed RasV12-expressing cells with reduced ERK signaling show hyperactivation of the PI3K/AKT pathway, GSK3b inhibition, c-MYC stabilization and expression of stem cell-associated genes. In these cells, the hyperactivation of the PI3K/AKT pathway is essential in order to maintain their transformed phenotype since pharmacological inhibition of the pathway abrogates their tumorigenicity. Collectively, these results demonstrate a novel anti-tumor effect of strong ERK signaling and suggest that processes attenuating ERK levels and/or activity may contribute to malignant transformation of oncogenic RAS-expressing cells. Therefore, we propose a model where a moderated level of activated ERK (p-ERK) in RAS-expressing cells promotes transformation whereas higher levels limit cancer initiation by activating tumor-supressive mechanisms. This model suggests caution in clinical use of inhibitors of the ERK-MAPK pathway. Although complete pathway shut-down may counter tumorigenesis, partial reductions in ERK signaling may be deleterious by allowing a bypass of tumor-suppressive mechanisms in other premalignant lesions or in cells with strong ERK activity. Citation Format: Xavier Deschênes-Simard, Filippos Kottakis, Frédéric Lessard, Nabeel Bardeesy, Gerardo Ferbeyre. Downregulation of PI3K signaling by high ERK activity prevents transformation by oncogenic RAS. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A09.
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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) | 0.003 | 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".