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

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.

Keywords: PTH1R; PTHrP; PTHrP/PTH1R signaling; cancer metastasis; targeted therapy.

Figure 1

The functional domains of the PTHrP protein. The signal peptide module serves to dock the nascent peptide to the secretory pathway. “PTH-like” indicates the receptor-binding region, and “Mid-region” contains the bipartite NLS essential for PTHrP nuclear import; the C-terminal domains include “osteostatin”, which is involved in bone turnover and β-arrestin binding. The green region is part of the C-terminal that only exists in PTHrP 1–173 [61]. PTH: parathyroid hormone; PTHrP: parathyroid hormone-related protein; PKA: protein kinase A; PKC: protein kinase C; NLS: nuclear localization signals; GPCR: G-protein-coupled receptors.

Figure 2

Diagram of ligand binding with PTH1R and the downstream signaling pathway. When PTH or PTHrP binds to PTH1R, it induces a conformational change in the receptor, leading to the activation of diverse downstream signal transduction pathways, via either G protein-dependent or -independent/β-arrestin-dependent mechanisms [52]. GEF: guanine nucleotide exchange factor; PLD: phospholipase D; MMP: matrix metalloproteinase; EGFR: epidermal growth factor receptor; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; PKA: protein kinase A; PKC: protein kinase C; PLC-β: phospholipase C-β; DAG: diacylglycerol; IP3: inositol 1,4,5-triphosphate.

Figure 3

The two-site model describes the interaction between PTHrP/PTH and PTH1R interaction mechanism. In this model, PTHrP (or PTH) binds to the extracellular domain (ECD) of the PTH1R at the juxtamembrane region, and then interacts with the transmembrane domain of the receptor to induce intracellular signaling. This model is supported by experimental evidence showing that mutations in the juxtamembrane region of PTH1R impair the binding of PTHrP to the receptor and downstream signaling [52].

Figure 4

Current and prospective approaches to target PTHrP/PTH1R.