Metformin inhibits the progression of castration-resistant prostate cancer by regulating PDE6D induced purine metabolic alternation and cGMP / PKG pathway activation.

The castration-resistant prostate cancer (CRPC) remains an incurable disease. Metformin has demonstrated a potential therapeutic effect on CRPC. However, the poor clinical performance of metformin against cancer may be due to its clinical dose being much lower than the anticancer concentration used in pre-clinical experiments. The challenge is to determine a way to enhance sensitivity to metformin at an appropriate concentration on CRPC. In this study, a mouse model of low-dose metformin treatment for CRPC cells were established. Metabolomic-seq and transcriptomic-seq was used to investigate changes in CRPC xenografts. We discovered that low-dose metformin inhibits the progression of CRPC by regulating PDE6D, which induces alterations in purine metabolism and activates the cGMP/PKG pathway. Furthermore, we found that cells with high expression of PDE6D were more resistant to metformin. When combined with the PDE6D inhibitor TMX-4100, the inhibitory effect on tumors was enhanced, and TMX-4100 demonstrated favorable biosafety in animal models. In conclusion, we found that low-dose metformin inhibits the progression of CRPC by regulating PDE6D-induced alterations in purine metabolism and activating the cGMP/PKG pathway. Moreover, patients with high PDE6D expression may exhibit greater resistance to metformin. Combining metformin with TMX-4100 could further improve the inhibitory effects on tumors.