A Cyanobacteria-Derived RNA Aptamer Resensitizes Prostate Cancer to Hormone Therapy

Abstract

Prostate adenocarcinoma resistance to androgen receptor (AR) The antitumor activity of the aptamer helped support L-Gln as an signaling inhibitor therapy is associated with elevated glutamine oncometabolite in prostate adenocarcinoma that can be targeted (L-Gln). Glutamine sensors, present in conserved riboswitches to sensitize tumors to hormone therapy. (glnA), control nitrogen metabolism in many organisms, such as cyanobacteria. Iterative in silico modifications of glnA found in Significance: Depletion of glutamine, which can mediate Synechococcus elongatus and thermodynamic analysis of a 56mer hormone therapy resistance in prostate cancer patients, with a aptamer resulted in high L-Gln specificity and affinity. The op- cyanobacteria-derived catalytic aptamer blocks FGF8 expression timized aptamer depleted L-Gln from prostate adenocarcinoma and sensitizes hormone refractive prostate tumors to androgen cells by both L-Gln sequestration and extracellular glutaminase receptor inhibitors. activation, serving as an allosteric activator. Glutamine depletion reduced FOXM1 transcriptional occupancy on the promoter of Glutamine-Gln FGF8, a known mediator of prostate adenocarcinoma castration induced prostate resistance. A point mutation in the binding pocket of the 56mer adenocarcinomaexpansion Au rendered the aptamer ineffective in L-Gln binding and FGF8 regulation. Accordingly, the L-Gln–depleting aptamer, with FGF8 Glutaminase demonstrated serum stability, limited the proliferation and pro-Tumor Iterative moted cell death of castration-resistant prostate adenocarcinoma modeling & alone and in combination therapy with AR antagonists, enzalu- Gln testing FOXM1 tamide and apalutamide, in subcutaneous and orthotopic mouse FGF8 models. Further selective tumor targeting was achieved by funcHigh-affinity tionalizing gold nanoparticles with either the optimized L-Gln Gln binding aptamer is an aptamer or the point-mutant aptamer. Castration sensitivity CAF allosteric was restored by the L-Gln–depleting aptamer but not by the glutaminase point-mutant aptamer. The functionalized nanoparticle demon-activator strated superior antitumor efficacy in an orthotopic prostate Created in BioRender. Bhowmick, N. (2025) https://BioRender.com/59zafcr adenocarcinoma model compared with the untargeted aptamer.