Targeting nucleotide exchange to inhibit constitutively active G protein ? subunits in cancer cells.

ABSTRACT: Constitutively active G protein ? subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active G? subunits in these disorders has yet to be achieved. We found that constitutively active G?q in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate-for-guanosine triphosphate (GDP/GTP) exchange to trap constitutively active G?q in inactive, GDP-bound G??? heterotrimers. Allosteric inhibition of other G? subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active G?q, FR inhibited second messenger signaling, arrested cell proliferation, reinstated melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF-driven UM cells. FR promoted UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)-mediated gene silencing, a heretofore unrecognized effector system of constitutively active G?q in UM. Constitutively active G?q and PRC2 therefore provide therapeutic targets for UM. The development of FR analogs specific for other G? subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active G? subunits or multiple G protein-coupled receptors (GPCRs) where targeting a single receptor is ineffective.

SUBMITTER: Onken MD 

PROVIDER: S-EPMC6279241 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature