Evaluation of the effect of DAPT and XAV939 micromolecules in in-hibiting NOTCH and WNT signaling pathways in melanoma

Abstract

Melanoma is the most serious type of skin cancer that can occur anywhere on the skin or near a mole. Melanoma can spread quickly throughout the body. The aim of the following plan is to treat melanoma through the stimulation of stem cells. Recent studies show that cancer stem cells are responsible for metastasis, drug resistance and tumor recurrence. These characteristics of stem cells are attributed to disruption of cellular signaling pathways such as Notch and Wnt, and targeting these pathways can bring new therapeutic achievements for cancer; But so far, the role of Notch and Wnt pathways in melanoma stem cells has not been well clarified. The most important pathways that are evaluated in the treatment of these cells are Hedgehog, Wnt, Notch and Hippo pathways. Notch pathway deregulation has been reported in many types of malignancies and solid tumors, including breast, ovary, neck, lung, pancreas, and medulloblastoma. Therefore, inhibiting the Notch pathway may provide an effective treatment for cancer. The Wnt signaling pathway is evolutionarily conserved and plays an important role in embryonic development, stability and regeneration of adult tissue. Two parts dependent on beta-catenin and non-dependent on beta-catenin in the Wnt signaling pathway are involved in the growth and proliferation and migration of stem cells. According to the good results obtained in the study of the inhibition of these signaling pathways on various cancers in This study has investigated the inhibitory effects of these signaling pathways in melanoma, and significant results have been obtained, which are mentioned below.

Materials & Methods: In the first part of our study, melanocytes from metastatic cell line A375 were cultured. Then, the self-renewal power of these cells has been investigated by the sphere and colony formation method. In the next part, the genes related to the pathways (HES1, HES5, Notch), Notch and Wnt (β-catenin, cyclinD1, c-Myc) were studied and the cells were treated with micromolecules. DAPT has been treated as a Notch pathway inhibitor and XAV939 as a Wnt pathway inhibitor. Finally, melanocytes were treated with the combination of these micromolecules. Results: The expression of Wnt and Notch genes has increased in real time PCR on colonized melanoma cells, and DAPT and XAV939 micromolecules inhibited the growth of tumor cells in specific concentrations.