Repurposing Salmon Calcitonin for Glioblastoma treatment: Targeting YAP/TAZ via Hippo pathway activation

Background Glioblastoma (GBM) remains a deadly brain tumor. Activation of the wild-type calcitonin receptor (CTR) by salmon calcitonin (sCT) suppresses glioma growth, whereas patient-derived CTR mutants drive tumor progression and correlate with poor survival. This study delineates the mechanisms underlying sCT-mediated tumor suppression and reveals structural defects in oncogenic CTR variants. Methods Proteome analysis of sCT-treated glioma cells was done to dissect the altered signaling. Multiple experimental approaches were used to elucidate the signaling behind CTR-dependent Hippo pathway activation. The therapeutic efficacy of sCT on the growth of human/murine glioma stem-like cells (GSC)-initiated tumors in an orthotopic mouse glioma model was assessed. Extensive microsecond-scale all-atom molecular dynamics simulations were performed to elucidate the structural impairments in CTR mutants. Results sCT treatment activated Hippo signaling as demonstrated by enhanced phosphorylation and subsequent degradation of YAP/TAZ and suppressed glioma growth through cAMP/PKA/LATS1 signaling in vitro. However, GSCs expressing a phosphorylation-resistant YAP mutant were refractory to sCT treatment in vitro. Both human and murine GSCs exhibited elevated CTR expression, and intranasal administration of sCT effectively inhibited the growth of GSC-initiated tumors. Furthermore, molecular dynamics simulations revealed structural perturbations in CTR interactions with either CT or the Gα subunit. Conclusions We establish that activation of the sCT–CTR axis suppresses glioma growth by inhibiting YAP/TAZ through Hippo pathway activation. We further delineate the structural aberrations responsible for the functional loss in patient-derived CTR mutants. Thus, we present compelling evidence supporting the therapeutic repurposing of calcitonin for GBM treatment.