Abstract
Rapamycin, also known as sirolimus, inhibits the mTOR pathway in complex diseases such as cancer, and its downstream targets are ribosomal S6 kinases (RPS6K). Sirolimus is involved in regulating cell growth and cell survival through roles such as the mediation of epidermal growth factor signaling. However, the systemic efficacy of sirolimus in pathway regulation is unclear. The purpose of this study is to determine systemic drug efficacy using computational methods and drug-induced datasets. We suggest a computational method using gene expression datasets induced by sirolimus and an inverse algorithm that simultaneously identifies parameters referring to gene–gene interactions. We downloaded two sirolimus-induced microarray gene expression datasets and used a computational method to obtain the most enriched pathway, then adopted an inverse algorithm to discover the gene–gene interactions of that pathway. In the results, RPS6KB1 was a target gene of sirolimus and was associated with genes in the pathway. The common gene interactions from two datasets were a hub gene, RPS6KB1, and 10 related genes (AKT3, CBLC, MAP2K7, NRG1/2, PAK3, PIK3CD/G, PRKCG, and SHC3) in the epidermal growth factor (ERBB) signaling pathway.
Highlights
Rapamycin, which possesses immunosuppressive and anti-proliferative properties, was discovered in 1964 as an antifungal metabolite produced by Streptomyces hygroscopicus [1]
Instead of the mammalian target of rapamycin (mTOR) signaling pathway, we considered the ERBB signaling pathway as the pathway most affected by sirolimus
We observed 18 overlapping genes between the mTOR pathway, which consisted of 48 genes, and the ERBB signaling pathway, which consisted of 87 genes, based on the KEGG pathway [15]
Summary
Rapamycin, which possesses immunosuppressive and anti-proliferative properties, was discovered in 1964 as an antifungal metabolite produced by Streptomyces hygroscopicus [1]. Known as sirolimus, has been reported to have many effects on cancer, diabetes, obesity, and genetic disorders [1,2]. Sirolimus was discovered to be an inhibitor of S6K1 activation [1–5] and identified as a mammalian target of rapamycin (mTOR). It downregulates cancer metabolism by inhibiting the oncogenic activation of the mTOR signaling pathway. In the mTOR signaling pathway, some genes, including phosphatidylinositol3-kinase (PI3K), protein kinase B (AKT), and phosphatase and tensin homologue (PTEN), play role as triggers for the activation of cell survival, proliferation and cell growth [8]. Its therapeutic potential against certain cancers, including gastric cancer, non-small cell lung cancer, and breast cancer [8–10], has been evaluated
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