Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis.
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.
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China; Postdoctoral research station of Neurosurgery, Wuhan General Hospital of Guangzhou Command, PLA, Wuhan, China.
Zhiguo
Z
Zhang
Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.
Lin
L
Wu
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Julei
J
Wang
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Gang
G
Li
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Dayun
D
Feng
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Bin
B
Zhang
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Lihong
L
Li
Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Jiandong
J
Yang
Postdoctoral research station of Neurosurgery, Wuhan General Hospital of Guangzhou Command, PLA, Wuhan, China.
Lianting
L
Ma
Department of Neurosurgery and Institute for Functional Brain Disorders, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
Huaizhou
H
Qin
D017209:Apoptosis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*
C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt