Opposing Effects of PI3K/Akt and Smad-Dependent Signaling Pathways in NAG-1-Induced Glioblastoma Cell Apoptosis

Abstract

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) is a divergent member of the transforming growth factor-beta (TGF-β) superfamily. NAG-1 plays remarkable multifunctional roles in controlling diverse physiological and pathological processes including cancer. Like other TGF-β family members, NAG-1 can play dual roles during cancer development and progression by negatively or positively modulating cancer cell behaviors. In glioblastoma brain tumors, NAG-1 appears to act as a tumor suppressor gene; however, the precise underlying mechanisms have not been well elucidated. In the present study, we discovered that overexpression of NAG-1 induced apoptosis in U87 MG, U118 MG, U251 MG, and T98G cell lines via the intrinsic mitochondrial pathway, but not in A172 and LN-229 cell lines. NAG-1 could induce the phosphorylation of PI3K/Akt and Smad2/3 in all six tested glioblastoma cell lines, except Smad3 phosphorylation in A172 and LN-229 cell lines. In fact, Smad3 expression and its phosphorylation were almost undetectable in A172 and LN-229 cells. The PI3K inhibitors promoted NAG-1-induced glioblastoma cell apoptosis, while siRNAs to Smad2 and Smad3 decreased the apoptosis rate. NAG-1 also stimulated the direct interaction between Akt and Smad3 in glioblastoma cells. Elevating the level of Smad3 restored the sensitivity to NAG-1-induced apoptosis in A172 and LN-229 cells. In conclusion, our results suggest that PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced glioblastoma cell apoptosis.

GDF15 induced apoptosis and cytotoxicity in A549 cells depends on TGFBR2 expression

“…Furthermore, silencing TGFBR2 inhibited GDF15 activation of caspase 9 and caspase 3 in these cells. These results are in agreement with the results of other studies . Suppression of TGFBR2 by specific siRNA induced apoptosis via increasing cleavage of caspase 9 and 3 in A549 cells; this data is in agreement with previous findings and is in contradiction to other studies .…”

“…These results are in agreement with the results of other studies. [32][33][34] Suppression of TGFBR2 by specific siRNA induced apoptosis via increasing cleavage of caspase 9 and 3 in A549 cells; this data is in agreement with previous findings 25,26 and is in contradiction to other studies. [35][36][37] Thus, the presence of TGFBR2 can mediate GDF15 inhibitory effect on cell proliferation.…”

NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development

“…Finally, we analyzed how GDF-15 inhibits NF-κB in macrophages. Limited evidence exists that GDF-15 signals through the canonical TGF-β receptor and pathway (21)(22)(23). Phospho-SMAD2 and -3 (pSMAD2 and pSMAD3) mediate activation of canonical TGF-β signaling while the noncanonical pathway of TGF-β signals through the activation of phosphorylated TGF-β-activated kinase (pTAK1), leading to further downstream activation of NF-κB or the p38 MAP kinase (24,25).…”

Cigarette smoke extract induces apoptosis of rat alveolar Type II cells via the PLTP/TGF-β1/Smad2 pathway

“…Smad2, as the downstream effector of TGF-β1, can be activated by TGF-β1. Zhang and colleagues have reported that siRNAs to Smad2/Smad3 can partly abrogate the phosphoinositide 3-kinase (PI3k) inhibitor-promoted NAG-1-induced glioblastoma cell apoptosis [20]. Yang provided the first evidence that Smad2, but not Smad3, plays a critical role in TGF-β-induced apoptosis and gene expression [21].…”