P5CS represses tumor progression via inhibiting assembly of 48S pre-translation initiation complex.

Δ1-Pyrroline-5-carboxylate synthase (P5CS), therate-limiting enzyme in the proline biosynthesis, has been implicated in diverse physiology and pathology, including cancer. However, whether P5CS exerts functions beyond its enzymatic activity has remained unclear. Here, we identify P5CS as a non-canonical RNA-binding protein that inhibits cancer cell growth and metastasis by inhibiting translation initiation in an enzyme-activity-independent manner in human cancer cells and cell-derived xenograft mouse models. Mechanistically, P5CS binds to the 5' untranslated region (UTR) of oncogenic mRNAs and disrupts the recruitment of eukaryotic translation initiation factor (eIF) 3a/3d-containing 43S preinitiation complex to cap-binding complex eIF4F, thereby blocking 48S assembly and subsequent global protein synthesis. Loss of P5CS accelerates the translational efficiency of IGF1R and promotes tumor progression. Collectively, our study highlights a non-canonical function of P5CS in translational regulation and the emerging non-metabolic functions of metabolic enzymes in tumorigenesis.