Figure 1.

Multiple molecular interactions in prostate cancer cells. PSMA is internalized upon ligand binding, in this case the radiolabeled small molecule ¹⁷⁷Lu-PSMA-617. The ligand is transported to the perinuclear region for degradation and releases its β-radiation to induce ds breaks. The PSMA molecule is recycled and released to the cell surface. Testosterone binds to the AR in the cytoplasm. The AR–testosterone complex binds to binding motifs on the DNA and ensures HR. If suppressed by AA or enzalutamide, unbound AR binds to the PSMA enhancer and promotor region and upregulates PSMA expression. PSMA has enzymatic properties and releases free glutamate from polyglutamated folate (B9). B9 is transported into the cell via the FR and aids with proliferation. Free glutamates activate GPCRs, which downstream activate IP3K if not inhibited by PTEN. Via IP3K-mediated conversion of PIP2 to PIP3, activated IP3K–AKT–mTOR signaling promotes proliferation and tumor cell growth. In BRCA1/2-mutated cells, PARP is upregulated and strongly induces DDR. PARPi counteracts PARP-mediated DDR. Black arrows and grey letters indicate normal function; red arrows and letters indicate drug-mediated functions. 177LU: 177Lutetium; PSMA: prostate-specific membrane antigen; AA: abiraterone actetate; DHT: dihydroxy-testosterone; T: testosterone; HR: homologous recombination; ds: double-strand; Glu: glutamate; FR: folate receptor; GPCR: G-protein-coupled receptor; PIP2: phosphatidylinositol-4, 5-bisphosphate; PIP3: phosphatidylinositol-3, 4, 5-triphosphate; IP3K: inositol 1,4,5-trisphosphate 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; PTEN: phosphatase and tensin homolog on chromosome ten; PARP: poly(ADP-ribose)-polymerase; PARPi: PARP inhibitor; BRCA1/2mu: breast cancer 1/2 mutation; HR: homologous recombination; DDR: DNA-damage repair. This figure was generated using biorender, www.biorender.com, accessed on 8 July 2021.