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Molecular and Cellular Biology, April 2003, p. 2407-2414, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2407-2414.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Caveolin-Induced Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Increases Arsenite Cytotoxicity

Sonsoles Shack,1,2 Xian-Tao Wang,1 Gertrude C. Kokkonen,1 Myriam Gorospe,1 Dan L. Longo,2 and Nikki J. Holbrook1,3*

Laboratory of Cellular and Molecular Biology,1 Laboratory of Immunology, National Institute on Aging-IRP, National Institutes of Health, Baltimore, Maryland 21224,2 Department of Internal Medicine, Section of Geriatrics, Yale University School of Medicine, New Haven, Connecticut 065113

Received 9 August 2002/ Returned for modification 23 September 2002/ Accepted 7 January 2003

The inhibitory effect of caveolin on the cellular response to growth factor stimulation is well established. Given the significant overlap in signaling pathways involved in regulating cell proliferation and stress responsiveness, we hypothesized that caveolin would also affect a cell's ability to respond to environmental stress. Here we investigated the ability of caveolin-1 to modulate the cellular response to sodium arsenite and thereby alter survival of the human cell lines 293 and HeLa. Cells stably transfected with caveolin-1 were found to be much more sensitive to the toxic effects of sodium arsenite than either untransfected parental cells or parental cells transfected with an empty vector. Unexpectedly, the caveolin-overexpressing cells also exhibited a significant activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which additional studies suggested was likely due to decreased neutral sphingomyelinase activity and ceramide synthesis. In contrast to its extensively documented antiapoptotic influence, the elevated activity of Akt appears to be important in sensitizing caveolin-expressing cells to arsenite-induced toxicity, as both pretreatment of cells with the PI3K inhibitor wortmannin and overexpression of a dominant-negative Akt mutant markedly improved the survival of arsenite-treated cells. This death-promoting influence of the PI3K/Akt pathway in caveolin-overexpressing cells appeared not to be unique to sodium arsenite, as wortmannin pretreatment also resulted in increased survival in the presence of H2O2. In summary, our results indicate that caveolin-induced upregulation of the PI3K/Akt signaling pathway, which appears to be a death signal in the presence of arsenite and H2O2, sensitizes cells to environmental stress.

* Corresponding author. Mailing address: Department of Internal Medicine, Yale University School of Medicine, 300 George St., Room 8100, New Haven, CT 06511. Phone: (203) 737-5847. Fax: (203) 737-1801. E-mail: Nikki.Holbrook{at}yale.edu.

Molecular and Cellular Biology, April 2003, p. 2407-2414, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2407-2414.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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