Anagrelide remodels the PDE3A–SLFN12 interactome to associate with translation initiation machinery in cancer cell lines

ABSTRACT: The phosphodiesterase 3A (PDE3A) modulator anagrelide induces complex formation between PDE3A and Schlafen 12 (SLFN12), leading to tRNA degradation, stress signaling, and apoptosis in cancer cells expressing both proteins. Because PDE3A forms signalosome complexes with multiple proteins in diverse cellular compartments, the effects of its modulation are expected to depend on the surrounding protein network. Here, we mapped the interactomes of PDE3A, SLFN12, and the anagrelide-induced PDE3A-SLFN12 complex by proximal biotinylation in two human cancer cell lines, and show that anagrelide promotes relocalization of the complex to ribosomes, induces interactions with translation initiation factors eIF3A and eIF3B, and reduces associations with proteasome and chaperonin complexes. Computational modeling suggests that the complex binds near the mRNA entry channel of the 40S ribosomal subunit. This study contributes to advancing the development of PDE3A modulators as therapeutic agents by providing a broader mechanistic understanding of their effects on surrounding protein–protein interaction networks.

SUBMITTER: Sami Salmikangas 

PROVIDER: S-BIAD3037 | bioimages |

REPOSITORIES: bioimages