Features | Partner Sites | Information | LinkXpress
Sign In
JIB
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING

Loss of Regulatory Enzyme Spurs Kidney Cancer Growth

By BiotechDaily International staff writers
Posted on 31 Jul 2014
Image: A metabolic enzyme has an unexpected role in regulating gene expression in kidney cancer. Primary human kidney tissue: FBP1 protein (green); cell nuclei (blue) (Photo courtesy of the University of Pennsylvania).
Image: A metabolic enzyme has an unexpected role in regulating gene expression in kidney cancer. Primary human kidney tissue: FBP1 protein (green); cell nuclei (blue) (Photo courtesy of the University of Pennsylvania).
Cancer researchers have found that the enzyme fructose-1,6-bisphosphatase 1 (FBP1) is missing or inactive in the clear cell renal cell carcinoma (ccRCC) form of kidney cancer, a lack that gives the cancer cells a metabolic advantage over surrounding normal tissue.

FBP1 is a gluconeogenesis regulatory enzyme that catalyzes the hydrolysis of fructose1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. Fructose-1,6-diphosphatase deficiency is associated with hypoglycemia and metabolic acidosis.

Investigators at the University of Pennsylvania (Philadelphia, USA) have been working with a mouse ccRCC model. Previous studies had shown that kidney tumors of this type were characterized by elevated glycogen levels and fat deposition. Development of these characteristics was associated with elevated expression of hypoxia inducible factors (HIFs) and mutations in the von Hippel-Lindau (VHL) encoded protein, pVHL, which occurs in 90% of ccRCC tumors.

The VHL protein (pVHL) is involved in the regulation of hypoxia inducible factor 1 alpha (HIF1alpha). This is a subunit of a heterodimeric transcription factor that at normal cellular oxygen levels is highly regulated. Under normal physiological conditions, pVHL recognizes and binds to HIF1alpha only when oxygen is present due to the post translational hydroxylation of two proline residues within the HIF1alpha protein. pVHL is an E3 ligase that ubiquitinates HIF1alpha and causes its degradation by the proteasome. In low oxygen conditions or in cases of VHL disease where the VHL gene is mutated, pVHL does not bind to HIF1alpha. This allows the subunit to dimerize with HIF1beta and activate the transcription of a number of genes, including vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin, and genes involved in glucose uptake and metabolism.

In the current study, which was published in the July 20, 2014, online edition of the journal Nature, the investigators used an integrative approach comprising metabolomic profiling and metabolic gene set analysis to examine more than 600 kidney tumors from human patients. They determined that FBP1 was uniformly depleted in all of the ccRCC tumors examined. The human FBP1 locus was found to reside on chromosome 9q22, the loss of which was associated with poor prognosis for ccRCC patients.

FBP1 was found in the nucleus of normal cells, where it bound to HIF to modulate its effects on tumor growth. In cells lacking FBPI, rapidly growing tumor cells were found to produce energy up to 200 times faster than normal cells.

“This study is the first stop in this line of research for coming up with a personalized approach for people with clear cell renal cell carcinoma-related mutations,” said senior author Dr. Celeste Simon, professor of cell and developmental biology at the University of Pennsylvania. “Since FBP1 activity is also lost in liver cancer, which is quite prevalent, FBP1 depletion may be generally applicable to a number of human cancers.”

Related Links:
University of Pennsylvania



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: The five stages of biofilm development: (1) Initial attachment, (2) Irreversible attachment, (3) Maturation I, (4) Maturation II, and (5) Dispersion. Each stage of development in the diagram is paired with a photomicrograph of a developing P. aeruginosa biofilm. All photomicrographs are shown to same scale (Photo courtesy of Wikimedia Commons).

Ionic Liquids Disperse Bacterial Biofilms and Increase Antibiotic Susceptibility

The ionic liquid choline-geranate was shown to effectively eliminate the protective biofilm generated by bacteria such as Salmonella enterica and Pseudomonas aeruginosa and to significantly increase the... Read more

Therapeutics

view channel
Image: Hair follicle (blue) being attacked by T cells (green) (Photo courtesy of Christiano Lab/Columbia University Medical Center).

Hair Restoration Method Clones Patients’ Cells to Grow New Hair Follicles

Researchers have developed of a new hair restoration approach that uses a patient’s cells to grow new hair follicles. In addition, the [US] Food and Drugs Administration (FDA) recently approved a new drug... Read more

Lab Technologies

view channel

Important Immune Cell Regulators’ Response Identified

A new strategy could help accelerate laboratory research and the development of potential therapeutics, including vaccines. The technology may also be used to identify the genes that underlie tumor cell development. There are approximately 40,000 genes in each of the body’s cells, but functions for only approximately... Read more

Business

view channel

Partnership Established to Decode Bowel Disease

23andMe (Mountain View, CA,USA), a personal genetics company, is collaborating with Pfizer, Inc. (New York, NY, USA), in which the companies will seek to enroll 10,000 people with inflammatory bowel disease (IBD) in a research project designed to explore the genetic factors associated with the onset, progression, severity,... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.