Abstract B235: The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to vemurafenib in melanoma.
Bibliographic record
Abstract
Abstract In eukaryotic cells, mRNA translation is restricted by the translation initiation step, in which eIF4E has been regarded as a master regulator. Overexpression of eIF4E has been found in different cancer types; however, whether eIF4E is involved in melanoma tumorigenesis and resistance to standard of care in melanoma remains unclear. We hypothesize that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the B-raf inhibitor, Vemurafenib. From our preliminary data, we show that by genetically knocking down eIF4E via siRNA or by using a pharmacological inhibitor of eIF4E, 4EGI-1, we can significantly repress the proliferation of a subset of melanoma cell lines. In addition, eIF4E activity contributes to the proliferation of some melanoma cell lines with acquired resistance to Vemurafenib, since siRNA-silencing eIF4E decreases their proliferation. Similarly, 4EGI-1 seems to be more effective at inhibiting cell proliferation of Vemurafenib resistant lines compared to their parental controls. Finally, we found that autophagy may act as a pro-survival mechanism in melanoma cell lines, based on the observation that the autophagy inhibitors Chloroquine, Bafilomycin, and 3-MA can repress cell proliferation in both BRAF V600E and BRAF WT cell lines. Further investigation with qPCR and western blot showed that eIF4E expression can be significantly downregulated at the mRNA and protein levels with inhibition of autophagy. This implies a role for eIF4E in mediating the pro-survival autophagy pathway in melanoma. Moreover, the expression of key autophagy markers, such as Atg5 and LC-3 II have been upregulated in several Vemurafenib resistant cell lines compared to the parental A375. In conclusion, our data show that eIF4E promotes proliferation of some melanoma cell lines. We also show that eIF4E is involved in maintaining the survival of some melanoma cell lines with acquired vemurafenib resistance. These data suggest that therapeutically targeting eIF4E, and disrupting pro-survival autophagy, may be a viable means of inhibiting melanoma cell proliferation and overcoming vemurafenib resistance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B235. Citation Format: Yao Zhan, Michael S. Dahabieh, Sonia V. del Rincon, Wilson H. Miller, Jr.. The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to vemurafenib in melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B235.
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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 | 0.000 | 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) | 0.000 | 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".