Parathyroid Hormone-Related Protein/Parathyroid Hormone Receptor 1 Signaling in Cancer and Metastasis

SIMPLE SUMMARY: The impact of parathyroid hormone-related protein (PTHrP) and parathyroid hormone receptor 1 (PTH1R or PTHR1) on cancer initiation, growth, and metastasis has been extensively documented in a number of in vitro and in vivo studies. Despite these findings, the attempts to target PTHrP/PTH1R signaling in cancer therapy have not produced successful results in the clinical setting. In light of these conflicting data and conclusions, this review seeks to provide a comprehensive examination of the role of PTHrP/PTH1R in cancer progression and metastasis, as well as offer insights for future research efforts in this field. ABSTRACT: PTHrP exerts its effects by binding to its receptor, PTH1R, a G protein-coupled receptor (GPCR), activating the downstream cAMP signaling pathway. As an autocrine, paracrine, or intracrine factor, PTHrP has been found to stimulate cancer cell proliferation, inhibit apoptosis, and promote tumor-induced osteolysis of bone. Despite these findings, attempts to develop PTHrP and PTH1R as drug targets have not produced successful results in the clinic. Nevertheless, the efficacy of blocking PTHrP and PTH1R has been shown in various types of cancer, suggesting its potential for therapeutic applications. In light of these conflicting data, we conducted a comprehensive review of the studies of PTHrP/PTH1R in cancer progression and metastasis and highlighted the strengths and limitations of targeting PTHrP or PTH1R in cancer therapy. This review also offers our perspectives for future research in this field.