Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines

Abstract

Human parathyroid hormone-related protein (hPTHrP), identified in patients with paraneoplastic hypercalcemia and expressed by different cell types during development and adult life, plays important roles in many human neoplasms. Immunohistochemical and RT-PCR analyses of hPTHrP and human parathyroid hormone receptor type 1 (PTHR-1) in primary medulloblastoma confirmed their expression in both classic and desmoplastic variants at RNA and protein levels. To evaluate the functional role of hPTHrP, DAOY and D283 medulloblastoma and U87MG glioma cells, expressing high levels of hPTHrP and PTHR-1, were treated with anti-sense oligonucleotides for hPTHrP. Anti-sense treatment produced in all cell lines a decrease of cell proliferation and clonogenic activity and an increase of apoptosis, while addition of exogenous hPTHrP (1-37) prevented these effects. Anti-sense induced the increase of Caspase-3, Fas (CD95) mRNAs and Bax/Bcl-2 mRNA ratio after 12 h of cell treatment. Exogenous hPTHrP (1-37) increased intracellular Ca(2+) concentration in DAOY cells as revealed by FURA. Anti-sense treated cells showed a significant decrease of steady-state levels of intracellular Ca(2+), which was reverted by addition of exogenous hPTHrP (1-37). This study indicates that hPTHrP and PTHR-1 are expressed in medulloblastoma and could promote tumor growth, protecting cells from apoptosis.

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

“…In 2007, Gessi et al [37] produced evidence of high constitutive secretion of PTHrP by DAOY medulloblastoma cells. On the other hand, cell treatment with PTHrP antisense oligonucleotides resulted in a drastic decrease of cell proliferation and in the activation of the apoptotic program with an increase of Fas and caspase 3 transcription rates, Bax/Bcl-2 ratio and intracellular Ca ++ levels.…”

Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

“…Specific PTHrP siRNA affects the CDC2 and CDC25B cell cycle -regulating genes implicated in the progression from S-G 2 phase to the mitotic phase (34). PTHrP was shown to protect cells from apoptosis by treating a human medulloblastoma with antisense PTHrP (42). PTHrP also regulates the synthesis of the antiapoptotic protein Bcl2 in HEK293 cells, and inhibits the apoptosis induced in chondrogenic cells and HEK 293 cells by TNFa (43,44).…”

Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues

“…Consequently, only limited information is currently available concerning the cellular and subcellular localisation of the PTHR1 receptor in human tissues. These reports comprise investigations on giant cell tumours (25), chondrosarcoma (8), ameloblastoma (26), medulloblastoma (27), prostate cancer (13), breast cancer (28,29) and gastric cancer (30). To the best of our knowledge there are currently no more extensive studies involving other human tumour species and investigating different types of tumours in parallel.…”