Essential role of caveolae in interleukin-6- and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells

Klaus Podar, Yu-Tzu Tai, Craig E Cole, Teru Hideshima, Martin Sattler, Angela Hamblin, Nicholas Mitsiades, Robert L Schlossman, Faith E Davies, Gareth J Morgan, Nikhil C Munshi, Dharminder Chauhan, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

126 Citations (Scopus)

Abstract

Caveolae, specialized flask-shaped lipid rafts on the cell surface, are composed of cholesterol, sphingolipids, and structural proteins termed caveolins; functionally, these plasma membrane microdomains have been implicated in signal transduction and transmembrane transport. In the present study, we examined the role of caveolin-1 in multiple myeloma cells. We show for the first time that caveolin-1, which is usually absent in blood cells, is expressed in multiple myeloma cells. Analysis of myeloma cell-derived plasma membrane fractions shows that caveolin-1 is co-localized with interleukin-6 receptor signal transducing chain gp130 and with insulin-like growth factor-I receptor. Cholesterol depletion by beta-cyclodextrin results in the loss of caveola structure in myeloma cells, as shown by transmission electron microscopy, and loss of caveolin-1 function. Interleukin-6 and insulin-like growth factor-I, growth and survival factors in multiple myeloma, induce caveolin-1 phosphorylation, which is abrogated by pre-treatment with beta-cyclodextrin. Importantly, inhibition of caveolin-1 phosphorylation blocks both interleukin-6-induced protein complex formation with caveolin-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. beta-Cyclodextrin also blocks insulin-like growth factor-I-induced tyrosine phosphorylation of insulin-responsive substrate-1 and downstream activation of the phosphatidylinositol 3-kinase/Akt-1 pathway. Therefore, cholesterol depletion by beta-cyclodextrin abrogates both interleukin-6- and insulin-like growth factor-I-triggered multiple myeloma cell survival via negative regulation of caveolin-1. Taken together, this study identifies caveolin-1 and other structural membrane components as potential new therapeutic targets in multiple myeloma.

Original languageEnglish
Pages (from-to)5794-5801
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number8
DOIs
Publication statusPublished - 21 Feb 2003
Externally publishedYes

Keywords

  • Caveolae/drug effects
  • Cell Survival/drug effects
  • Cholesterol/metabolism
  • Humans
  • Insulin-Like Growth Factor I/pharmacology
  • Interleukin-6/pharmacology
  • Multiple Myeloma/pathology
  • Protein Serine-Threonine Kinases/metabolism
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins/pharmacology
  • Signal Transduction/drug effects
  • Tumor Cells, Cultured

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