Caveolin-1 controls cell proliferation and cell death by suppressing expression of the inhibitor of apoptosis protein survivin

Abstract

Caveolin-1 is suggested to act as a tumor suppressor. We tested the hypothesis that caveolin-1 does so by repression of survivin, an Inhibitor of apoptosis protein that regulates cell-cycle progression as well as apoptosis and is commonly overexpressed in human cancers. Ectopic expression of caveolin-1 in HEK293T and ZR75 cells or siRNA-mediated silencing of caveolin-1 in NIH3T3 cells caused downregulation or upregulation of survivin mRNA and protein, respectively. Survivin downregulation in HEK293T cells was paralleled by reduced cell proliferation, increases in G0-G1 and decreases in G2-M phase of the cell cycle. In addition, apoptosis was evident, as judged by several criteria. Importantly, expression of green fluorescent protein-survivin in caveolin-1-transfected HEK293T cells restored cell proliferation and viability. In addition, expression of caveolin-1 inhibited transcriptional activity of a survivin promoter construct in a β-catenin-Tcf/Lef-dependent manner. Furthermore, in HEK293T cells caveolin-1 associated with β-catenin and inhibited Tcf/Lef-dependent transcription. Similar results were obtained upon caveolin-1 expression in DLD1 cells, where APC mutation leads to constitutive activation of β-catenin-Tcf/Lef-mediated transcription of survivin. Taken together, these results suggest that anti-proliferative and pro-apoptotic properties of caveolin-1 may be attributed to reduced survivin expression via a mechanism involving diminished β-catenin-Tcf/Lef-dependent transcription.

The Caveolin-1 Connection to Cell Death and Survival

“…Caveolin-1 expression and intracellular distribution depend on cell-cell adhesion in a manner related to that observed for -catenin [78][79]. Indeed, studies have now implicated Caveolin-1 as a negative regulator of -catenin-Tcf/Lef-dependent transcription [28,[80][81]. Although it remains unclear whether the interaction between Caveolin-1 and -catenin is direct or indirect, recruitment of -catenin to caveolae and/or Caveolin-1-containing protein complexes at the cell surface is thought to preclude -catenin Tcf/Lef-dependent transcription of target genes [28,[81][82].…”

Caveolin-1, E-cadherin and β-catenin in gastric carcinoma, precancerous tissues and chronic non-atrophic gastritis

“…Burgermeister, et al [9] reported that the overall caveolin-1 mRNA and protein were decreased in 74% and 54% gastric carcinoma patients, respectively. Furthermore, recent evidences showed that caveolin-1 was implicated in the pathogenesis of oncogenic cell transformation and tumorigenesis through Wnt signaling pathway by regulating β-catenin location [9][10][11][12] Chu, et al…”

“…is an essential structural protein that acts as a tumor modulator regulating cells proliferation, differenttiation, apoptosis, adhesion, and invasion by interacting with cell adhesion molecules and signaling receptors [3][4][8][9][10][11] . E-cadherin and β-catenin as a complex are specifically involved in the regulation of epithelial cell-to-cell adhesion and they have a close relationship with the invasion and metastasis ability of cancer [6,7,[12][13][14][15] .…”

Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway

“…However, our data ruled out this possibility. Survivin, a member of the inhibitor of apoptosis gene family, is expressed in a cell cycle-dependent manner, increasing in the G2/M phase of the cell cycle followed by a rapid decline in the G1 phase [26,27]. Recent studies have revealed that quercetin inhibits cell proliferation by causing cell cycle arrest in G2/M phase [28,29].…”