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Parathyroid Hormone–Related Peptide Signaling in Cancer

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Cell Signaling & Molecular Targets in Cancer

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Abstract

Parathyroid hormone–related protein (PTHrP) was discovered in 1987 as a systemic humoral factor because of its association with the paraneoplastic syndrome of humoral hypercalcemia of malignancy (HHM). However, despite the control of hypercalcemia, the presence of HHM is associated with a poor prognosis in cancer patients. It became clear that PTHrP was expressed in almost all tissues where it regulates cell growth and differentiation, smooth muscle relaxation, and transepithelial calcium transport. In cancer, PTHrP behaves like a growth factor, regulating tumor cell growth and invasion and promoting cancer progression and metastasis spreading. In particular, in bone microenvironment, PTHrP expression supports a vicious cycle, leading to progressive bone destruction and cancer burden increase. The effects of PTHrP on cancer cells are multifaceted and reflect the fact that the native molecule can be processed into peptides that mediate pleiotropic actions through many molecular pathways. PTHrP functions in paracrine and/or autocrine manner through type 1 parathyroid (PTH)/PTHrP receptor (PTH1R), which is a G protein–coupled receptor (GPCR) belonging to the secretin-like GPCR family (class B) located at the cell membrane and in the nuclear nucleoplasm. PTHrP activated PTH1R signals to downstream effectors through pathways mediated by G protein-PKA/PLCβ and through G protein–independent pathways mediated by β-arrestins. Moreover, PTHrP also exerts intracrine effects. The midregion domain of its molecule contains a bipartite nuclear localization signal through which it translocates into the nucleus and regulates, like a transcription factor, target genes. To further complicate the mechanisms of action of PTHrP, its role as a gene transcription factor for the nuclear PTH1R whose localization in the nuclear or cytoplasmic compartment is regulated by the presence (binding?) of PTHrP has been recognized. This review article highlights some recent advances in the understanding of the signaling pathways involved in the PTHrP functions and of the factors that regulate PTHrP expression in cancer cells.

*This work was supported in part by grant D1.1-2008 to F.O. Ranelletti from Università Cattolica del S. Cuore.

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Authors and Affiliations

  1. Institute of Histology and Embryology, Università Cattolica del S. Cuore, Rome, 00168, Italy

    Franco Oreste Ranelletti

  2. Institutes of Human Anatomy and Cell Biology, Universtà Cattolica del S. Cuore, Largo F. Vito 1, 00168, Rome, Italy

    Giovanni Monego

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  1. Franco Oreste Ranelletti
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  2. Giovanni Monego
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Correspondence to Franco Oreste Ranelletti .

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  1. , Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India

    Malay Chatterjee

  2. , Division of Biochemistry & Chemistry, City University of New York Medical Scho, New York, 10031, New York, USA

    Khosrow Kashfi

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Ranelletti, F.O., Monego, G. (2012). Parathyroid Hormone–Related Peptide Signaling in Cancer. In: Chatterjee, M., Kashfi, K. (eds) Cell Signaling & Molecular Targets in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0730-0_4

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