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Contribution of caveolin-1 and Akt to TNF--induced cell death

¹Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto 612-8555; Departments of ²Cardiology and ³Pharmacology, Research Institute, National Cardiovascular Center, Osaka 565-8565; and ⁴Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

Submitted 27 August 2003 ; accepted in final form 5 March 2004

We used retrovirus insertion-mediated random mutagenesis to generate tumor necrosis factor- (TNF-)-resistant lines from L929 cells. Using this approach, we discovered that caveolin-1 is required for TNF--induced cell death in L929 cells. The need for caveolin-1 in TNF--induced cell death was confirmed by the restoration of sensitivity to TNF- after ectopic reconstitution of caveolin-1/ expression. This caveolin-1-mutated line was also resistant to H₂O₂ and staurosporine, but not to lonidamine. HepG2 cells are known to lack endogenous caveolins. HepG2 cells stably transfected with caveolin-1/ were found to be much more sensitive to TNF- than either parental cells transfected with caveolin-1 or parental cells transfected with an empty vector. In contrast to its extensively documented antiapoptotic effect, the elevated activity of Akt appears to be important in sensitizing caveolin-1-expressing cells to TNF-, since pretreatment of cells with the phosphatidylinositide 3-kinase (PI3K) inhibitor LY-294002 or wortmannin completely blocked PI3K activation and markedly improved the survival of TNF--treated L929 cells. The survival rates of caveolin-1-normal and caveolin-1-deficient L929 cells were comparable after treatment with PI3K inhibitor and TNF-. Similar results were obtained with HepG2 cells that stably expressed caveolin-1/ or - and parental cells transfected with an empty vector. In summary, our results indicate that caveolin-1 preferentially sensitizes L929 cells to TNF- through the activation of a PI3K/Akt signaling pathway.

caveolin; tumor necrosis factor; phosphatidylinositol 3-kinase

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