Pheophorbide Suppresses Prostate Tumorigenesis by Targeting the PRMT5/WDR77 Signaling

Protein arginine methyltransferase 5 (PRMT5) forms a complex with WDR77 in the cell cytoplasm and is required for growth of prostate epithelial cells as well as prostate cancer cells. Two breakdown products (pheophorbide a and pheophorbide b) of chlorophyll were identified as natural inhibitors of PRMT5 and suppressed proliferation of prostate cancer cells. In this report, pheophorbide a (PPBa) was shown to induce degradation of the WDR77 protein in a ubiquitin proteasome-dependent manner. The molecular docking predicted that PPBa binds the WDR77 protein with a high affinity (ΔG = −9.0 kcal/mol) via hydrogen bonds and hydrophobic interaction with amino acid residues in WDR77. The PPBa treatment of mouse prostate tumors induced by loss of the Pten gene reduced the PRMT5 enzymatic activity, WDR77 protein stability, Ki67 proliferation index, and tumors to hyperplasia. This study provides useful information regarding the application of natural products as therapeutic reagents for prostate cancer prevention and treatment.