Background/Aim: Cancer-induced bone pain (CIBP) is one of the most common symptoms of bone metastasis of tumor cells. The hypothalamus may play a pivotal role in the regulation of CIBP. However, little is known about the exact mechanisms. Materials and Methods: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured. Results: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist. Conclusion: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.
Neuropeptides are endogenous neuromodulators that have been shown to play pivotal roles in cancer initiation and progression. The phosphorylation/dephosphorylation processes are critically involved in regulating the bioactivity of peptides. This study designed chiral phosphorylated neuropeptides with distinct modification sites to examine the stereochemical regulatory mechanisms of alkaline phosphatase-mediated dephosphorylation and its biological effects on glioblastoma (GBM). The differential dephosphorylation catalyzed by alkaline phosphatase (ALP) demonstrates that both the spatial positions and quantity of modification sites significantly influence aggregation kinetics and intermolecular interactions. The dephosphorylated products derived from d-enantiomer probes inhibit GBM proliferation and invasion by disrupting cytoskeletal reorganization, while simultaneously enhancing tumor-targeted accumulation capacity and prolonging in vivo metabolic stability. These findings provide crucial insights into the stereochemical effects of chirality and terminal phosphorylation sites on peptide functionality, as well as contribute to the development for Y1R-targeted therapies for GBM and other solid tumors.
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