Molecular Mechanisms Implicated in the Pro Survival Action of Caveolin1

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The phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway has recently emerged as a major target for regulation by caveolin-1 in a variety of cancer cells [12,13,86]. A possible role of caveolin-1 in PI3K/Akt pathway activation was shown in multiple myeloma cells which, unlike most other hematopoietic-derived cells, express high levels of caveolin-1 [86]. Caveolin-1 was found to co-localize in lipid rafts fractions, and to co-exist in an immunoprecipitable complex, with receptors for insulin-like growth factor-I (IGF-I) and interleukin-6 (IL-6). These cell survival-inducing factors stimulated c-Src-mediated phosphorylation of caveolin-1 on Tyr14 and its association with PI3K subunits. The disruption of lipid raft organization by cholesterol depletion resulted in a redistribution of caveolin-1 and PI3K, an inhibition of Tyr14 phosphorylation of caveolin-1, and an abrogated IGF-I- and IL-6-induced activation of Akt and survival, thus confirming that both caveolin-1 and intact caveolae are essential for these processes [86]. Consistent with this conclusion, transient expression of caveolin-1 in LNCaP human prostate cancer cells resulted in elevated Akt phosphorylation and activation and increased resistance to thapsigargin-induced apoptosis [12]. Similarly, stable expression of caveolin-1 in MCF-7 human breast cancer cells also resulted in elevated basal phosphorylation of Akt, concomitantly increasing cellular resistance to anoikis [13].

Interestingly, a correlation between caveolin-1 expression and Akt activation was also seen in HEK-293 human embryonic kidney cells [82] and L929 mouse fibrosarcoma cells [81] although, in the latter two cases, Akt activation was reported to sensitize the cells to the apoptotic stimuli.

The mechanisms whereby caveolin-1 regulates PI3K/Akt-mediated cell survival have yet to be fully elucidated. It is clear, however, that caveolin-1 may influence this important pathway by recruiting and/or modulating its various components at different levels. First, caveolin-1 may act at the receptor level, as shown in caveolin-1-expressing MCF-7 cells, in which IGF-I receptor expression is elevated [13]. In these cells, the up-regulation of IGF-I receptors is associated with enhanced IGF-I signaling to the Erk1/2 and PI3K/Akt pathways (Fig. 12.1). In endothelial cells, caveolin-1 promotes the nongenomic action of nuclear receptors such as the estrogen receptor-a (ERa), resulting in activation of Akt and endothelial nitric oxide synthase (eNOS) [87]. Whether a similar mechanism operates in steroid-dependent human cancers, such as breast cancer and prostate cancer, has yet to be determined. In endothelial cells, caveolin-1 similarly interacts with TNF-a receptors,

Cell Prosurvivial Image
Fig. 12.1 Enhanced IGF-I-mediated signaling in caveolin-1-transfected MCF-7 breast adenocarcinoma cells. Cells were serum-starved for 24 h and then stimulated with 50 ng mL-1 human IGF-I for the indicated times. Cell lysates were resolved by SDS-PAGE and then

blotted with antibodies to the active phos-pho-Erk1/2 (pErk1/2), Erk1/2, phospho-Akt (pAkt) and actin (loading control) as indicated. (Figure reprinted, with permission, from [13].)

allowing TNF-a-induced activation of Akt [88]. An essential role of caveolin-1 in avp3 integrin-dependent activation of PI3K and Akt upon mechanical stress was recently noted also in VSMC [89]. In these cells, caveolin-1 is additionally required for angiotensin II receptor transactivation of the EGF receptor after Racl and NADPH oxidase activation, resulting in Akt activation [90]. Caveolin-1 is part of a survival signaling complex comprising urokinase-type plasminogen activator receptor, integrin avp3/a5p1 and the SFK Yes in vitronectin-attached endothelial cells [91].

As mentioned above, caveolin-1 recruits both regulatory and catalytic subunits of PI3K upon IGF-I and IL-6 stimulation in multiple myeloma cells [86]. Phosphoino-sitide-dependent protein kinase-1 (PDK1), which mediates Akt Thr308 phosphorylation was also found physically to interact with caveolin-1 [92]. However, in this case a caveolin-1 scaffolding peptide suppressed the self-phosphorylation and the in-vitro kinase activities of PDK1. These results are inconsistent with the data showing that caveolin-1 significantly increases the activity of PDK1 and Akt [12]. Chun and co-workers suggested that these differences may result from changes in both subcellular localization and in the affinity to caveolin-1 of PDK1 compared to other factors (such as the serine/threonine protein phosphatases) [92]. Integrin-linked kinase has been proposed to serve as an Akt Ser473-kinase, and was found to interact with caveolin-1 via a CSD-binding motif [93,94]. Intriguingly, another putative Akt Ser473 kinase, namely DNA-PK, is localized in part in lipid rafts, although in this case direct interaction with caveolin-1 has yet to be demonstrated [95].

Finally, caveolin-1 may regulate the PI3K/Akt pathway by affecting lipid and protein phosphatases that turn the pathway off. Interaction of caveolin-1 via its CSD with protein phosphatases that dephosphorylate phospho-Akt, namely PP1 and PP2A, results in their inhibition and in consequent activation of Akt in LNCaP

cells [12]. Caveolin-1 is also associated with the tumor suppressor protein PTEN, a 3-phosphoinositide phosphatase that terminates the PI3K-dependent signal, although in this case the effect of caveolin-1 on PTEN activity has not been determined [96]. Interestingly, it was shown recently that caveolin-1 knockout up-reg-ulates PTEN expression in TRAMP mouse prostate tumors, consistent with the inhibition of tumor progression caused by loss of caveolin-1 in this model [84].

The PI3K/Akt pathway is not the only survival pathway that is regulated by caveolin-1. Although caveolin-1 usually inhibits growth factor activation of the mitogenic Erk1/2 pathway, it is required for integrin-dependent activation of Erk1 / 2 through a complex that consists of Fyn, Shc, and Grb2 [97,98]. The Erk1/2 pathway promotes cell survival, at least in some cell types [99,100]. Caveolin-1 is similarly required for p1-integrin-mediated signaling to Src kinases and focal adhesion kinase (FAK) and, consequently, b1-integrin-dependent adhesion [101]. Caveolin-1 enables activation of c-Src upon cross-linking of the cell adhesion protein CE-CAM6 in BxPC3 human pancreatic adenocarcinoma cells, as well as c-Src-depend-ent tyrosine phosphorylation of FAK and the consequent inhibition of anoikis [85]. A positive regulatory role of caveolin-1 on survival signaling may also be implied by data showing that it interacts with a component of the TNF-a-NFkB pathway [102], and that it may inhibits a caveolae-resident neutral sphingomyelinase via its CSD sequence [103].

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