Phosphorylated 4E-BP1 is associated with poor survival in melanoma

Kathryn E. O'Reilly, Melanie Warycha, Michael A. Davies, Vanessa Rodrik, Xi K. Zhou, Herman Yee, David Polsky, Anna C. Pavlick, Neal Rosen, Nina Bhardwaj, Gordon Mills, Iman Osman

    Research output: Contribution to journalArticle

    54 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)2872-2878
    Number of pages7
    JournalClinical Cancer Research
    Volume15
    Issue number8
    DOIs
    StatePublished - Apr 15 2009

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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    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. (2009). Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clinical Cancer Research, 15(8), 2872-2878. https://doi.org/10.1158/1078-0432.CCR-08-2336