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Critical Reviews™ in Eukaryotic Gene Expression
IF: 2.156 5-Year IF: 2.255 SJR: 0.649 SNIP: 0.599 CiteScore™: 3

ISSN Print: 1045-4403
ISSN Online: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukaryotGeneExpr.v15.i1.20
pages 15-28

Parathyroid Hormone-Related Protein in Prostate Cancer

Farrokh Asadi
Medical Service, VA Chicago Health Care System, Department of Medicine, University of Illinois College of Medicine, Chicago IL 60612
Subhash Kukreja
Medical Service, VA Chicago Health Care System, Department of Medicine, University of Illinois College of Medicine, Chicago IL 60612

ABSTRACT

Although originally discovered as the peptide responsible for humoral hypercalcemia of malignancy (HHM), parathyroid hormone-related protein (PTHrP) has been shown to play a major role in fetal development. In the adult, it is widely distributed in normal and various cancer tissues. In spite of the rarity of HHM in prostate cancer, PTHrP is widely distributed in prostate cancer cells. PTHrP is a precursor molecule with generation of various fragments with distinct biological activities. More recent studies have shown that there is intranuclear localization of PTHrP and that intracrine effects of the peptide are involved in promoting processes that result in tumor progression (cell proliferation, apoptosis, cell attachment and angiogenesis) in prostate cancer. PTHrP expression is controlled by three distinct promoters, with P3 being used most often in cancer cells. The factors that control PTHrP production via interaction with the promoters are growth factors, androgens, vitamin D analogs, and adenoviral proteins. TGF-β and its effector Smad3 activate the P3 promoter through an AGAC box and an Ets binding site involving Ets1 and to some extent Ets2 proteins. In addition, TGF-β stimulates P3 promoter activity via Smad-independent pathways that involve the p38 MAP kinase. Although the addition of PTHrP or transfection with the PTHrP gene in prostate cells results in effects that promote tumor development, studies that employ inhibition of PTHrP activity in vitro and in vivo are needed to establish a definitive role of this peptide in the pathogenesis of prostate cancer.


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