To identify novel therapeutic targets, it is important to uncover pathways essential to neuroblastoma tumorigenesis. The AKT pathway is of specific interest since it is related to various tyrosine kinase receptors currently targeted by a number of anticancer drugs . Our study confirmed that the AKT pathway was activated in neuroblastoma but failed to demonstrate a correlation amongst this activation and prognostic variables, in contrast to a preceding study . This distinction could be explained in portion by the distinct methodologies utilised, including the amount of core biopsies per tumor, doublecontrol evaluation by independent pathologists, quantification of constructive cells, and statistical design addressing the problem of clinical correlations. Nonetheless, in our study, the degree of AKT protein expression was correlated using a poorer outcome, exactly where event cost-free survival was drastically lower in individuals displaying a high level of AKT. A important correlation was observed between PIK, an AKT activator, and pAKT, the activated form of AKT.
Moreover, downstream proteins were present in greater than of principal tumors and metastases, a higher expression confirming AKT pathway activation. Our data recommended that, amongst the tyrosine kinase receptors, TRKB, PDGFR , and IGFR might possibly represent targets of interest for specific therapeutic intervention. We also found that VEGF and VEGFR had moderate but frequent expression, the important correlation among the molecule and its receptor strongly IOX2 selleck chemicals suggesting paracrine and autocrine activation . With respect for the EGF receptor loved ones, our outcomes indicated that HER and EGFR expressions have been particularly rare in neuroblastoma and showed no correlation with clinical findings, in concordance using a preceding study but contrary to others . In the AKT inhibitors tested, only LY and RAD drastically decreased neuroblast survival and induced a G cell cycle arrest. RAD is a precise mTOR inhibitor; it most likely blocks AKT activation by inhibiting the formation of mTOR complex ; mTOR complicated is recognized to phosphorylate and activate AKT .
In neuroblastoma and acute myeloid leukemia, RAD also decreased cell survival. TRX , which activates the AKT pathway, partially reversed the action of RAD, LY, and doxorubicin. Several research have demonstrated that chemosensitivity to doxorubicin was regulated by the AKT pathway . PTEN is a tumor suppressor protein that negatively regulates the PIK AKT signaling pathway Lopinavir by dephosphorylating phosphatidylinositol kinase . Despite the fact that located in several malignancies , mutations inside the PTEN gene are rare in neuroblastoma and might possibly be responsible for malignant progression in only a limited percentage of circumstances .