Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein.

Abstract

Germline inactivation of the VHL tumor suppressor gene is associated with an increased risk of clear cell carcinoma of the kidney in the context of von Hippel-Lindau (VHL) disease. Somatic VHL mutations are also common in nonhereditary (sporadic) clear cell carcinomas. The VHL protein (pVHL) has multiple functions that might be linked to tumor suppression, including targeting the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. HIF, especially HIF2alpha, appears to play a causal role in clear cell renal carcinogenesis based on genotype-phenotype correlations in VHL disease, laboratory experiments with human VHL-/- renal carcinoma cell lines, and genetically engineered mouse models. Deregulation of HIF almost certainly accounts for the high levels of vascular endothelial growth factor (VEGF) observed in kidney cancer and relates to their sensitivity to VEGF inhibitors. In addition, the beneficial effects of mammalian target of rapamycin (mTOR) inhibitors are likely due to, at least partly, their ability to down-regulate HIF. pVHL, in a HIF-independent manner, also regulates a specialized structure called the primary cilium and regulates apoptosis via factors such as NFkappaB. Loss of the primary cilium probably facilitates the development of preneoplastic renal cysts, whereas increased NFkappaB might contribute to the resistance of kidney cancers to conventional cytotoxic agents.

• Authors: William G Kaelin Jr
• Journal: Cancer (Cancer) Vol. 115 Issue 10 Suppl Pg. 2262-72 (May 15 2009) ISSN: 0008-543X [Print] United States
• PMID: 19402056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: (c) 2009 American Cancer Society.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• endothelial PAS domain-containing protein 1
• Von Hippel-Lindau Tumor Suppressor Protein

Topics

• Animals
• Apoptosis
• Basic Helix-Loop-Helix Transcription Factors (physiology)
• Carcinoma, Renal Cell (genetics)
• Drug Delivery Systems
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Kidney Neoplasms (genetics)
• Von Hippel-Lindau Tumor Suppressor Protein (physiology)