Galectin-3 Inhibits Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis by Activating Akt in Human Bladder Carcinoma Cells

Abstract

The antiapoptotic molecule galectin-3 was previously shown to regulate CD95, a member of the tumor necrosis factor (TNF) family of proteins in the apoptotic signaling pathway. Here, we question the generality of the phenomenon by studying a different member of this family of proteins [e.g., TNF-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a wide variety of cancer cells]. Overexpression of galectin-3 in J82 human bladder carcinoma cells rendered them resistant to TRAIL-induced apoptosis, whereas phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY-294002) blocked the galectin-3 protecting effect. Because Akt is a major downstream PI3K target reported to play a role in TRAIL-induced apoptosis, we questioned the possible relationship between galectin-3 and Akt. Parental J82 and the control vector-transfected J82 cells (barely detectable galectin-3) exhibit low level of constitutively active Akt, resulting in sensitivity to TRAIL. On the other hand, J82 cells overexpressing galectin-3 cells expressed a high level of constitutively active Akt and were resistant to TRAIL. Moreover, the blockage of TRAIL-induced apoptosis in J82 cells seemed to be mediated by Akt through the inhibition of BID cleavage. These results suggest that galectin-3 involves Akt as a modulator molecule in protecting bladder carcinoma cells from TRAILinduced apoptosis. (Cancer Res 2005; 65(17): 7546-53)

Synergistic Effects of PectaSol-C Modified Citrus Pectin an Inhibitor of Galectin-3 and Paclitaxel on Apoptosis of Human SKOV-3 Ovarian Cancer Cells

“…In agreement with this finding other studies reported that Gal-3 imparts resistance to apoptosis in breast, bladder and prostate cancer (Choi et al, 2004;Oka et al, 2005;Wang et al, 2010), by Bcl-2 up-regulation and inhibition of Gal-3 induced caspase-3 activity (Wang et al, 2010). Another report showed that use of Pect-MCP as a blocker of cell surface Gal-3 could induce apoptosis in prostate cancer by suppression of MAPK pathway (Yan and Katz, 2010).…”

“…This characteristic is unique among galectins and may be responsible for the interest in Gal-3 as a target molecule (Elola et al, 2007).The anti-apoptotic function of Gal-3 has been well demonstrated in variety of human cancers, such as breast, bladder and prostate (Choi et al, 2004;Oka et al, 2005;Wang et al, 2010). It has been demonstrated that Gal-3 knockout in PC3 prostate cancer cells could sensitize cells to chemotherapeutic drugs (Wang et al, 2010).…”

Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains

“…TRAIL represents a particularly promising anticancer agent because of its intrinsic selectivity toward cancer cells (18). At the same time, overactivation of intracellular antiapoptotic mechanisms has been shown to attenuate cancer cell sensitivity to TRAIL (19). Although U87MG cells are indeed resistant to TRAIL, we found that PIT-1 substantially sensitized U87MG cells to killing by TRAIL (Fig.…”

Galectin-3 in apoptosis, a novel therapeutic target

“…On the contrary, over-expression of galectin-3 in J82 human bladder carcinoma cells rendered them resistant to TRAIL induced apoptosis, whereas phosphatidylinositol3 kinase PI3K inhibitors (wortmannin and LY 294002) blocked the protecting effect of galectin-3. High levels of constitutively active Akt were seen in the galectin-3 over-expressing J82 cells suggesting that galectin-3 involves Akt as a modulator molecule in protecting bladder carcinoma cells from TRAIL induced apoptosis (Oka et al, 2005). It is reasonable to assume that observed inconsistencies are probably due to use of different cell lines.…”