Positive crosstalk between ERK and p38 in melanoma stimulates migration and in vivo proliferation

Authors

  • Yeriel Estrada,

    1.  Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine
    Search for more papers by this author
  • Jianli Dong,

    1.  Department of Oncological Science, Mount Sinai School of Medicine, New York, NY, USA
    Search for more papers by this author
    • *

      Current address: Department of Pathology and Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA

  • Liliana Ossowski

    1.  Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine
    Search for more papers by this author

Liliana Ossowski, e-mail: Liliana.Ossowski@mssm.edu

Summary

Melanoma is one of the most therapy-resistant cancers. Activating mutations in BRAF and NRAS are the source of extracellular signal regulated protein kinase (ERK) pathway activation. We show that melanoma cell lines, originating in different metastatic sites, with BRAF or NRAS mutations, in addition to active mitogen activated protein kinase (MAPK)–ERK, also have highly activated stress activated protein kinase (SAPK)-p38. This is in direct contrast to carcinoma cells in which the activity of the two kinases appears to be mutually exclusive; high level of p38 activity inhibits, through a negative feedback, ERK activity and prevents tumorigenesis. Melanomas are insensitive to ERK inhibition by p38 and utilize p38-signaling pathway for migration and growth in vivo. We found a positive functional loop linking the high ERK activity to surface expression of αVβ3-integrin. This integrin, by interacting with vitronectin, induces p38 activity and increases IL-8 production, enhancing cell migration. Because the negative loop from p38 to ERK is lost, the two kinases can remain simultaneously activated. Inhibition of ERK and p38 activities is more effective in blocking in vivo growth than inhibition of each kinase individually. Future therapies might have to consider targeting of both pathways.

Ancillary