PRKG۲ as a Potential Therapeutic Target for Eradicating Melanoma cell and Senescent Melanocytes: In silico study

Melanoma represents a challenging variant of cutaneous malignancy characterized by an inadequate therapeutic response. The accumulation of senescent cells has been documented to rise with increasing age and may play a significant role in the onset and progression of melanoma. In this regard, there exists a plethora of similarities between melanoma and cellular senescence. Furthermore, cellular senescence within melanoma cells can be triggered by anticancer treatments and may contribute to various treatment-related adverse events (TRAEs) . In this context, research has indicated that Senolytic agents, which are specifically designed to eradicate senescent cells, exhibit promising results with anticancer therapies. Consequently, the identification of therapeutic targets capable of eliminating both melanoma cells and senescent melanocytes not only aids in cancer prevention but may also enhance the efficacy of cancer treatments. Method: The gene expression profile of the dataset (GSE۱۲۲۹۰۷) encompasses microarray data of five melanocytes and five melanomas, in addition to expression data from four young and four senescent melanocytes (GSE۸۳۹۲۲) obtained from the Gene Expression Omnibus database. Subsequently, the Affy and limma packages within the R software environment were employed to determine differentially expressed genes (DEGs) within these two datasets. Moreover, the biological pathways mediated by the upregulated genes were illuminated through the EnrichR database. The identification of potentially druggable genes was conducted utilizing the Drug Gene Interaction Database (DGIdb) alongside the Gene Card database. Results: Importantly, a total of ۱۲۳۱ and ۴۲۴ genes were observed to exhibit significant upregulation in melanoma and senescent melanocytes, respectively. Then, ۲۱ genes were found to be commonly upregulated in these two cell types. These shared genes were significantly involved in the NGF-stimulated transcriptional pathway. Initially, the NGF pathway was recognized for its crucial role in neuronal development and functionality; however, it has now emerged as a vital contributor to the proliferation and survival of various tumor types . Further analysis revealed Histone-Lysine N-Methyltransferase PRDM۷, Protein Kinase CGMP-Dependent ۲ (PRKG۲), and Protein Tyrosine Phosphatase Receptor Type Z۱ (PTPRZ۱) as notable druggable proteins. Among these candidates, we prioritized the PRKG۲ protein due to its capacity to induce the expression of FOS, one of our commonly upregulated genes. FOS has been implicated as a regulator of cellular proliferation, differentiation, and transformation, and can activate the NGF pathway. Conclusion: This computational analysis has revealed PRKG۲ as a potentially effective therapeutic target for the removal of both senescent melanocytes and melanoma, thereby aiding in the progress of cancer prevention and treatment approaches.

کلیدواژه ها:

Melanoma ، senescent cells ، Senolytic ، PRKG۲ protein ، FOS