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

Abstract

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 H 2 O 2 . 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 H 2 O 2 , sensitizes cells to environmental stress.

Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype

“…These findings are supported by previous reports showing that caveolin 1 and 2 expression is associated with highly aggressive tumours such as inflammatory breast carcinoma (Eynden, 2005), basal-like (Savage et al, , 2008) and triple-negative breast carcinoma (Shack et al, 2003;Tan et al, 2007;Savage et al, 2007Savage et al, , 2008. Aside from breast, the association between caveolin expression and poor patient outcome was noticed in other tissue tumours (Savage et al, , 2008, including prostate (Karam et al, 2007), lung ((Ho et al, 2008), and the central nervous system (Barresi et al, 2006).…”

Dracorhodin Perchlorate Induces A375-S2 Cell Apoptosis via Accumulation of p53 and Activation of Caspases

“…The protective effect of wortmannin in our study also reflects a proapoptotic role of PI3-K. 51,52) It was reported that H 2 O 2 produced platelet-derived growth factor-b (PDGF-b) receptor tyrosine phosphorylation and downstream ATM kinase activation with profound p53 ser-15 phosphorylation involved in cell growth arrest and apoptosis, linking oxidative stress to p53 through the PDGF-b receptor and ATM. 53) In summary, the data presented here indicate that dracorhodin perchlorate induces apoptotic cell death in A375-S2 cells through accumulation of p53 and activation of caspases.…”

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

“…For example, PI3K is positively implicated in apoptosis induction in response to various stimuli, including hypoxia (23), arsenic compounds (24), glucose deprivation (25), and serum withdrawal (26). These findings indicate that PI3K activates two functionally opposite pathways, depending on cell type, nature of stimulus, and activities of other signaling pathways.…”