Essential Role of Caveolae in Interleukin-6- and Insulin-like Growth Factor I-triggered Akt-1-mediated Survival of Multiple Myeloma Cells

• Published in: The Journal of biological chemistry 2003-02, Vol.278 (8), p.5794-5801
• Main Authors: Podar, Klaus, Tai, Yu-Tzu, Cole, Craig E, Hideshima, Teru, Sattler, Martin, Hamblin, Angela, Mitsiades, Nicholas, Schlossman, Robert L, Davies, Faith E, Morgan, Gareth J, Munshi, Nikhil C, Chauhan, Dharminder, Anderson, Kenneth C
• Format: Article
• Language: English
• Subjects: Caveolae - drug effects; Caveolae - immunology; Caveolae - physiology; Cell Survival - drug effects; Cell Survival - immunology; Cell Survival - physiology; 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M208636200

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 β-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 β-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. β-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 β-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.