Parathyroid hormone-related peptide (PTHrP) is a secreted protein produced
by a variety of human cancers, including breast, prostate, lung, and renal carcinomas. Because
of its structural similarity to parathyroid hormone at the amino terminus, the two proteins
interact with a common cell surface receptor, the PTH/PTHrP receptor. When overproduced by
tumor cells, PTHrP enters the circulation, giving rise to the common paraneoplastic syndrome of
Humoral Hypercalcemia of Malignancy (HHM). Although initially discovered in malignancies, PTHrP
is now known to be produced by most cells and tissues in the body. It acts as an autocrine and
paracrine mediator of cell proliferation and differentiation, effects which are mediated via
the PTH/PTHrP receptor. Recent evidence also has shown that, directly following translation,
PTHrP is able to enter the nucleus and/or nucleolus and influence cell cycle progression and
apoptosis (intracrine effects). We are studying the effects of PTHrP on cell proliferation of
breast cancer cells. These studies are being addressed in two ways. In order to study the
autocrine/paracrine effects of the peptide, full-length PTHrP has been over-expressed in a
bacterial system and purified to homogeneity. In order to study the intracrine effects, PTHrP
cDNA has been cloned in an expression vector and stably transfected in breast cancer cells . We
have shown that PTHrP localizes to the nucleus and produces a net increase in breast cancer
cell proliferation. The mechanism for this effect is being investigated with respect to cell
cycle regulation.
The PTHrP gene is down-regulated by 1,25-dihydroxyvitamin D. The mechanism by which vitamin D
regulates PTHrP gene transcription is being studied at the molecular level. We are also
investigating whether non-calcemic vitamin D analogues can be developed as chemotherapeutic
agents to decrease PTHrP production by cancer cells, thereby eliminating hypercalcemia as well
as reversing the growth-stimulatory effects of the peptide on cancer cells. Since cancers which
over-produce PTHrP are more likely to metastasize to bone, reduced PTHrP secretion may also
reduce the likelihood of metastasis and improve the patient prognosis.
Narayanan
R, Tovar VA, Falzon M, Weigel NL. The functional consequences of cross talk between the
vitamin D receptor and ERK signaling pathways are cell specific. J Biol Chem 279:47298-47310,
2004.
Shen X, Qian L, Falzon M. PTH-related protein enhances MCF-7 breast cancer cell
adhesion, migration, and invasion via an intracrine pathway. Exp Cell Research 294:420-433,
2004.
Tovar VA, Falzon M. Prostate cancer cell type-specific regulation of the human PTHrP
gene via a negative VDRE. Mol Cell Endo 204:51-64, 2003.
Shen X, Falzon M. PTH-related protein modulates PC-3 prostate cancer cell adhesion and
integrin subunit profile. Mol Cell Endo 199:165-177, 2003.
Tovar VA, Falzon M. Regulation of parathyroid hormone-related protein gene expression by
vitamin D in PC-3 prostate cancer cells. Mol Cell Endo. 190:115-124, 2002.
Tovar VA, Shen X, Falzon M. Intracrine parathyroid hormone-related protein protects
against serum starvation-induced apoptosis and regulates the cell cycle in MCF-7 breast cancer
cells. Endocrinology 143:596-606, 2002. |
