Targeting PGE2 mediated senescent neuron improves tumor therapy.

Abstract

Background: Recent studies have highlighted bidirectional signaling between tumors and neurons; however, the interactions between tumors and neurons in response to radio-/chemotherapy remain obscure, which hampers the tumor treatment.

Methods: Glioblastoma organoids (GBOs) and primary neuron coculture, targeted metabonomics, RNA pulldown, mass spectrum, co-immunoprecipitation, RNA-sequencing, transcript/protein validations, and multi-electrode arrays were performed to analyze neuron-tumor interaction in response to therapy. In vivo validations were conducted in orthotopic mouse models. Diagnostic and prognostic values were evaluated in serum, tissue microarray as well as The Cancer Genome Atlas (TCGA).

Results: GBOs recruited and induced pro-tumor-survival senescent neurons upon radiation/chemotherapeutic treatment. Targeted metabonomics revealed that significantly increased tumor-derived prostaglandin E2 (PGE2) induced neuronal senescence phenotype. Screening of enzymes involved in PGE2 synthesis identified prostaglandin E synthase 3 (PTGES3) as the key enzyme responsible for PGE2 upregulation. Biochemical studies revealed that irradiation or chemotherapeutic drug-triggered asparagine endopeptidase (AEP) specifically cleaved eukaryotic translation initiation factor 4A1 (eIF4A1) to produce truncated C-terminal eIF4A1 (teIF4A1-C), which dissociated from DEAD-box helicase 6 (DDX6) and recruited eIF4A3 and polyadenylate-binding protein nuclear 1 (PABPN1) to promote the mRNA stability of PTGES3. Elevated PGE2 reciprocally enhanced AEP expression. Inhibiting PGE2 or AEP reduced neuronal senescence and delayed tumor progression. Strikingly, single-cell analysis further showed that expressions of AEP/PTGES3/EIF4A1 in tumor cells were consistent with senescent neuronal cyclin-dependent kinase inhibitor 1A (CDKN1A) in high-neuronal-connectivity glioblastoma. The serum PGE2 concentration was elevated after radiation and higher in resistant glioblastoma patients. High expression of PTGES3 was associated with a poor prognosis.

Conclusions: Our study revealed that the AEP/PGE2 feedback loop modulates tumor-induced neuronal senescence upon radio-/chemotherapy and highlights the therapeutic value to improve tumor therapy.