Pathogenesis of cancer is a multi-step process containing a number of cellular alterations such as post-translational dysregulation of intracellular signaling proteins. These alterations control several functions in carcinogenesis such as angiogenesis, metastasis, evading growth suppressors, and sustaining proliferative signaling. Data of various studies has demonstrated that Phosphatidylinositol 3-kinase (PI3K/AKT) and Mitogen-activated protein kinase (ERK/MAPK) pathways are both abnormally activated in many cancer types, including neuroblastoma. ERK/MAPK and PI3K/AKT signaling pathways that are regulated by sequential phosphorylation upon extracellular stimulation have many important functions in cell cycle, migration, proliferation and apoptosis. Besides their aberrant phosphorylation/activation, there is a crosstalk between these two pathways resulting in an anti-apoptotic effect. In this chapter, carcinogenetic abnormalities in post-translational regulation of the activity of ERK/MAPK and PI3K/AKT pathways in neuroblastoma and other cancers will be summarized. In addition, several crosstalk nodes between two pathways will be briefly explained. All these concepts are not only crucial for thoroughly understanding the molecular basis of carcinogenesis but also choosing the appropriate molecular targets for effective diagnosis and treatment.

One of the most important contributing factors for cancer development is the aberrant activation of mitogenic MAPK and AKT survival pathways. Abnormal activities of these pathways also indicates poor prognosis as a result of drug resistance in cancer treatment. It is revealed that there is a cross-talk between these two signaling cascades and they act together by one triggering the other performing an anti-apoptotic effect. It is evident that interplay between MAPK and AKT pathways is at the center of poor prognosis especially in neuroblastoma. However, it is still unknown what is there at the heart of this interaction. In this mini review, tumorigenic and chemotherapy-resistant effects of MAPK and AKT pathways and also the effect of their cross-talk in neuroblastoma and other cancers is summarized, Then, several cross-talk nodes between two pathways, which is used by the cells in a context-dependent mode is briefly explained. Finally, summarizing the studies giving insights about certain cell cycle regulators which may be involved in the intersection of these signaling pathways, importance of analyzing not only direct crosstalk between the members of these two pathways, but also mediator-dependent interactions are emphasized, since it is crucial to understand these interactions to choose the appropriate molecular targets for both diagnosis and treatment especially of neuroblastoma which has a very poor prognosis.

Objective: Targeted cancer therapy using targeted cell proliferation inhibitors has become increasingly more critical. Studies conducted over the last decade have shown that non-steroidal drugs containing salicylic acid (SA) such as aspirin reduce mortality in many cancers. From this perspective, there are data suggesting SA as a potential inhibitor of the mitogenic MEK1/2 (mitogen-activated-protein-kinase, MAPK), extracellular-signal regulated-protein-kinase (ERK)) signaling, which could be highly effective in the prevention of proliferation in cancer. To date, no study has been conducted on the effect of SA on MEK1/2 signaling in neuroblastoma cells. Thus, the aim of this study is to reveal whether SA has an effect on MEK1/2 signaling in neuroblastoma cancer which is a frequent pediatric cancer with poor prognosis. Materials and Methods: The purpose of this study was to investigate whether a SA analog acibenzolar-S-methyl had an effect on the MEK1/2 signaling pathway and on cell viability in SH-SY5Y neuroblastoma cells by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell viability analysis and MEK1/2 and active caspase-3 detection by western blotting technique. Results: MTS cell viability test indicated that 10 mM acibenzolar-S-methyl reduces cell viability by 50%. Western blotting results of 10 mM acibenzolar-S-methyl-treated cells showed that MEK1/2 signaling was significantly inhibited in SH-SY5H cells. Besides, an increase in active-caspase-3 levels provided insight into acibenzolar-S-methyl's apoptotic effect which needs further morphological apoptotic data. Conclusion: Our research is the first to show that SA analog acibenzolar-S-methyl negatively affects MEK1/2 signaling causing the death of SH-SY5Y neuroblastoma cells. Our results can give insight not only into understanding the mechanisms of carcinogenesis but also into developing effective treatment methods.