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

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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
Externally publishedYes

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Melanoma
Survival
Cell Line
Phosphorylation
Phosphatidylinositol 3-Kinase
Protein Array Analysis
Mutation
Proteins
Melanocytes
Mitogen-Activated Protein Kinases
Signal Transduction
Neoplasms
Research Design
Recurrence
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

O'Reilly, K. E., Warycha, M., Davies, M. A., Rodrik, V., Zhou, X. K., Yee, H., ... 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

Phosphorylated 4E-BP1 is associated with poor survival in melanoma. / O'Reilly, Kathryn E.; Warycha, Melanie; Davies, Michael A.; Rodrik, Vanessa; Zhou, Xi K.; Yee, Herman; Polsky, David; Pavlick, Anna C.; Rosen, Neal; Bhardwaj, Nina; Mills, Gordon; Osman, Iman.

In: Clinical Cancer Research, Vol. 15, No. 8, 15.04.2009, p. 2872-2878.

Research output: Contribution to journalArticle

O'Reilly, KE, Warycha, M, Davies, MA, Rodrik, V, Zhou, XK, Yee, H, Polsky, D, Pavlick, AC, Rosen, N, Bhardwaj, N, Mills, G & Osman, I 2009, 'Phosphorylated 4E-BP1 is associated with poor survival in melanoma', Clinical Cancer Research, vol. 15, no. 8, pp. 2872-2878. https://doi.org/10.1158/1078-0432.CCR-08-2336
O'Reilly KE, Warycha M, Davies MA, Rodrik V, Zhou XK, Yee H et al. Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clinical Cancer Research. 2009 Apr 15;15(8):2872-2878. https://doi.org/10.1158/1078-0432.CCR-08-2336
O'Reilly, Kathryn E. ; Warycha, Melanie ; Davies, Michael A. ; Rodrik, Vanessa ; Zhou, Xi K. ; Yee, Herman ; Polsky, David ; Pavlick, Anna C. ; Rosen, Neal ; Bhardwaj, Nina ; Mills, Gordon ; Osman, Iman. / Phosphorylated 4E-BP1 is associated with poor survival in melanoma. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 8. pp. 2872-2878.
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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.",
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AU - O'Reilly, Kathryn E.

AU - Warycha, Melanie

AU - Davies, Michael A.

AU - Rodrik, Vanessa

AU - Zhou, Xi K.

AU - Yee, Herman

AU - Polsky, David

AU - Pavlick, Anna C.

AU - Rosen, Neal

AU - Bhardwaj, Nina

AU - Mills, Gordon

AU - Osman, Iman

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N2 - 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.

AB - 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.

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