Phosphocaveolin-1 enforces tumor growth and chemoresistance in rhabdomyosarcoma

PLoS One. 2014 Jan 10;9(1):e84618. doi: 10.1371/journal.pone.0084618. eCollection 2014.

Abstract

Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caveolin 1 / genetics*
  • Caveolin 1 / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression
  • Heterografts
  • Humans
  • Mice
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rhabdomyosarcoma / genetics*
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology*
  • Tumor Burden / genetics
  • src-Family Kinases / metabolism

Substances

  • Caveolin 1
  • Protein Kinase Inhibitors
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases

Grants and funding

This work was supported by the Fondazione Cariplo grant to EM, Grant NEDD - Network Enabled Drug Design, Regione Lombardia to EM, “Associazione Italiana per la Ricerca sul Cancro” (MFAG Project n. 9161 to SM and Project 6021 to RD) and University of Brescia research fund (ex 60%) to AF and EM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.