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Abstract Background The biguanide metformin has been shown to not only reduce circulating glucose levels but also suppress in vitro and in vivo growth of prostate cancer. However, the mechanisms underlying the anti-tumor effects of metformin in advanced prostate cancers are not fully understood. The goal of the present study was to define the signaling pathways regulated by metformin in androgen-receptor (AR) positive, castration-resistant prostate cancers. Methods Our group used RNA sequencing (RNA-seq) to examine genes regulated by metformin within the C4–2 human prostate cancer cell line. Western blot analysis and quantitative RT-PCR were used to confirm alterations in gene expression and further explore regulation of protein expression by metformin. Results Data from the RNA-seq analysis revealed that metformin alters the expression of genes products involved in metabolic pathways, the spliceosome, RNA transport, and protein processing within the endoplasmic reticulum. Gene products involved in ErbB, insulin, mTOR, TGF-β, MAPK, and Wnt signaling pathways are also regulated by metformin. A subset of metformin-regulated gene products were genes known to be direct transcriptional targets of p53 or AR. Western blot analyses and quantitative RT-PCR indicated these alterations in gene expression are due in part to metformin-induced reductions in AR mRNA and protein levels. Conclusions Together, our results suggest metformin regulates multiple pathways linked to tumor growth and progression within advanced prostate cancer cells.