Parathyroid hormone-related protein is an essential growth factor for human clear cell renal carcinoma and a target for the von Hippel-Lindau tumor suppressor gene

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 1; pp. 180 - 188
• Main Authors: MASSFELDER, Thierry, LANG, Herve, SCHORDAN, Eric, LINDNER, Veronique, ROTHHUT, Sylvie, WELSCH, Sandra, SIMON-ASSMANN, Patricia, BARTHELMEBS, Mariette, JACQMIN, Didier, HELWIG, Jean-Jacques
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2004
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell Division; Growth Substances - genetics; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Medical sciences; Mice; Mice, Nude; Parathyroid Hormone-Related Protein - genetics; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumors; Ubiquitin-Protein Ligases - genetics; von Hippel-Lindau Disease - genetics; Von Hippel-Lindau Tumor Suppressor Protein; Kidney disease; Human; Clear cell carcinoma; Target; Urinary system disease; Targeting; Grawitz tumor; Parathyroid hormone related peptide; Malignant tumor; Essential; Growth factor; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-1968

Clear cell renal carcinoma (CCRC) is responsible for 2% of cancer-related deaths worldwide and is resistant to virtually all therapies, indicating the importance of a search for new therapeutic targets. Parathyroid hormone-related protein (PTHrP) is a polyprotein derived from normal and malignant cells that regulates cell growth. In the current study, we show that blocking PTHrP with antibodies or antagonizing the common parathyroid hormone (PTH)/PTHrP receptor, the PTH1 receptor, dramatically blunts the expansion of human CCRC in vitro by promoting cell death. Importantly, in nude mice, anti-PTHrP antibodies induced complete regression of 70% of the implanted tumors by inducing cell death. In addition, we demonstrate that the von Hippel-Lindau tumor suppressor protein, which functions as a gatekeeper for CCRC, negatively regulates PTHrP expression at the post-transcriptional level. These studies indicate that PTHrP is an essential growth factor for CCRC and is a novel target for the von Hippel-Lindau tumor suppressor protein. Taken together, these results strongly suggest that targeting the PTHrP/PTH1 receptor system may provide a new avenue for the treatment of this aggressive cancer in humans.