Phosphorylated 4E-BP1 is associated with poor survival in melanoma Journal Article
| Authors: | O'reilly, K. E.; Warycha, M.; Davies, M. A.; Rodrik, V.; Zhou, X. K.; Yee, H.; Polsky, D.; Pavlick, A. C.; Rosen, N.; Bhardwaj, N.; Mills, G.; Osman, I. |
| Article Title: | Phosphorylated 4E-BP1 is associated with poor survival in melanoma |
| Abstract: | Purpose: Both phosphatidylinositol 3-kinase/AKT and RAS/mitogen-activated protein kinase signal transduction pathways mediate 4E-BP1 phosphorylation, releasing 4E-BP1 from the mRNA cap and permitting translation initiation. Given the prevalence of PTEN and BRAF mutations in melanoma, we first examined translation initiation, as measured by phosphorylated 4E-BP1 (p-4E-BP1), in metastatic melanoma tissues and cell lines. We then tested the association between amounts of total and p-4E-BP1 and patient survival. Experimental Design: Seven human metastatic melanoma cells lines and 72 metastatic melanoma patients with accessible metastatic tumor tissues and extended follow-up information were studied. Expression of 4E-BP1 transcript, total 4E-BP1 protein, and p-4E-BP1 was examined. The relationship between 4E-BP1 transcript and protein expression was assessed in a subset of patient tumors (n = 41). The association between total and p-4E-BP1 levels and survival was examined in the larger cohort of patients (n = 72). Results: 4E-BP1 was hyperphosphorylated in 4 of 7 melanoma cell lines harboring both BRAF and PTEN mutations compared with untransformed melanocytes or RAS/RAF/PTEN wild-type melanoma cells. 4E-BP1 transcript correlated with 4E-BP1 total protein levels as measured by the semiquantitative reverse-phase protein array (P = 0.012). High levels of p-4E-BP1 were associated with worse overall and post-recurrence survival (P = 0.02 and 0.0003, respectively). Conclusion: Our data show that translation initiation is a common event in human metastatic melanoma and correlates with worse prognosis. Therefore, effective inhibition of the pathways responsible for 4E-BP1 phosphorylation should be considered to improve the treatment outcome of metastatic melanoma patients. © 2009 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; adult; cancer survival; controlled study; human tissue; protein expression; protein phosphorylation; middle aged; gene mutation; human cell; major clinical study; mutation; cancer recurrence; melanoma; metastasis; cell line, tumor; phosphorylation; phosphatidylinositol 3 kinase; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; neoplasm metastasis; initiation factor 4e binding protein 1; adaptor proteins, signal transducing; phosphoproteins; ras protein; b raf kinase; proto-oncogene proteins b-raf; paraffin |
| Journal Title: | Clinical Cancer Research |
| Volume: | 15 |
| Issue: | 8 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2009-04-15 |
| Start Page: | 2872 |
| End Page: | 2878 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-08-2336 |
| PUBMED: | 19336517 |
| PROVIDER: | scopus |
| PMCID: | PMC3995540 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus" |
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