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.
Highlights
Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1), a divergent member of the transforming growth factorbeta (TGF-b)/bone morphogenetic protein (BMP) superfamily, was identified by PCR-based subtractive hybridization in NSAIDtreated HCT-116 colorectal cancer cells [1]
These results demonstrate that NAG-1 can induce apoptosis in a restricted set of glioblastoma cell lines
It has been reported that NAG-1 expression in glioblastoma cell lines is significantly lower than in benign glioma cells and normal human astrocytes, and that primary glioblastoma have less NAG-1 expression compared to other gliomas [17] [18]
Summary
Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1), a divergent member of the transforming growth factorbeta (TGF-b)/bone morphogenetic protein (BMP) superfamily, was identified by PCR-based subtractive hybridization in NSAIDtreated HCT-116 colorectal cancer cells [1]. Due to identified by several other research groups, NAG-1 is designated as macrophage inhibiting cytokine 1 (MIC-1) [2], placental transformation growth factor beta (PTGFB) [3], prostate derived factor (PDF) [4], placental bone morphogenetic protein (PLAB) [5], growth differentiation factor-15 (GDF-15) [6], and PL74 [7]. The mature dimer is secreted into the extracellular media [8] [9]. A variety of signaling pathways may contribute to the stringent regulation of NAG-1 expression, secretion, and stromal storage [8] [9]
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