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.
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.
Massfelder
Thierry
T
Section of Renovascular Pharmacology and Physiology, Institut National de la Santé et de la Recherche Médicale-University Louis Pasteur, University Louis Pasteur School of Medicine, Strasbourg, France. thierry.massfelder@medecine.u-strasbg.fr
Lang
Herve
H
Schordan
Eric
E
Lindner
Veronique
V
Rothhut
Sylvie
S
Welsch
Sandra
S
Simon-Assmann
Patricia
P
Barthelmebs
Mariette
M
Jacqmin
Didier
D
Helwig
Jean-Jacques
JJ
D000818:Animals; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology*; D002455:Cell Division; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
D006133:Growth Substances; D044162:Parathyroid Hormone-Related Protein; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human