We show that the glial cell line-derived neurotrophic factor (GDNF) activates the PI3K/Akt-signaling pathway in human neuroblastoma cells that express functional Ret-receptor complexes.
The purpose of this study was to determine whether the phosphatidylinositol 3-kinase (PI3K)/Akt pathway can alter the expression of survivin and facilitate tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in neuroblastoma cells.
We hypothesize that VEGF will up-regulate survivin, a member of the IAP family of anti-apoptotic proteins, via the PI3K/Akt cell signaling pathway in human neuroblastoma cells.
Consistent with these observations, PI3K inhibition in MYCN-amplified human neuroblastoma cell lines resulted in decreased levels of Mycn protein without affecting levels of MYCN mRNA and caused decreased proliferation and increased apoptosis.
Treatment of NB cell lines with the histone deacetylase inhibitor trichostatin A led to increased gene transcription of four of the 30 genes, ERRFI1 (MIG-6), PIK3CD, RBP7 (CRBPIV) and CASZ1, indicating that these genes could be affected by epigenetic downregulation in NBs.
Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death.
In this study we investigated the phosphorylation status of key proteins in the PI3K/AKT/mTOR pathway and the effects of the mTOR inhibitors rapamycin and CCI-779 on neuroblastoma tumorigenesis.
Pharmacological inhibition of PI3K greatly reduced the ability of PDGF-BB to block gp120 IIIB-mediated apoptosis and cell death in human neuroblastoma cells.
These results suggest that repression of Survivin by FKHRL1 facilitates FKHRL1-induced apoptosis and sensitizes to cell death induced by DNA-damaging agents, which supports the central role of PI3K-PKB-FKHRL1 signaling in drug resistance of human NB.
The PI3K inhibitor PI103 cooperates with TRAIL to synergistically induce apoptosis (combination index < 0.1), to suppress clonogenic survival, and to reduce tumor growth in a neuroblastoma in vivo model.
Evaluation of the expression of these PI3K genes can predict aggressive disease, and indicates stage-dependent involvement of PI3K-pathway members in neuroblastoma.
Our previous studies have demonstrated that PI3K/AKT signaling is critical for the oncogenic transformations induced by gastrin-releasing peptide (GRP) and its receptor, GRP-R, in neuroblastoma.
Here, we show that p37δ, a kinase-dead isoform of the PI3K catalytic subunit p110δ, is over-expressed in neuroblastoma tumors, and that it correlates with the activation of both PI3K/Akt- and RAS-signaling pathways.
Moreover, inhibitors of PI3K/mTOR and GLI signaling reduced neuroblastoma cell growth, but no additional growth inhibitory effects were detected when the two classes of drugs were combined.
Here we demonstrate that PI3K/Akt pathway is crucial for the upregulation of P2X7R expression in serum-deprived neuroblastoma cells, circumstance that facilitates cell proliferation in the absence of trophic support.
We previously demonstrated that PI3K Class IIβ (PI3KC2β) and its regulator intersectin 1 (ITSN1) are highly expressed in primary NB tumors and cell lines.
However, NVP-BEZ235, a potent dual PI3K and mTOR inhibitor have not shown beneficial effects on neuroblastoma especially in terms of apoptosis induction as a single agent.
PI103 combined doxorubicin significantly inhibits the growth of established NB tumors, induced apoptosis of tumor cells, and improved the survival of mice in vivo Taken together, our findings suggest that PI3K inhibition seems to be a promising option to sensitize tumor cells for chemotherapy in NB, which may be effective in the treatment of NBs.