[HTML][HTML] Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis

Z Zhang, L Wu, J Wang, G Li, D Feng, B Zhang, L Li… - PloS one, 2014 - journals.plos.org
Z Zhang, L Wu, J Wang, G Li, D Feng, B Zhang, L Li, J Yang, L Ma, H Qin
PloS one, 2014journals.plos.org
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 …
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.
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