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

Disruption of Mitochondrial Enzyme Function Characterizes Some Cancers

By BiotechDaily International staff writers
Posted on 02 Jan 2012
Since mutations in the genome of cancer cells often force tumors to use metabolic pathways not found in normal cells, cancer researchers believe that drugs targeting these pathways will be able to destroy tumors with fewer adverse side effects.

Some tumors harbor mutations in the citric acid cycle (CAC or Krebs cycle) or electron transport chain (ETC) that disable normal oxidative mitochondrial function. In this regard investigators at Emory University (Atlanta, GA, USA) studied the relationship between the enzyme PDHK1 (pyruvate dehydrogenase kinase 1), an important point of control for cancer cell metabolism, and the tyrosine kinase FGFR1 (fibroblast growth factor receptor 1), which is activated in several types of cancer.

They reported in the December 23, 2011, online edition of the journal Molecular Cell that tyrosine phosphorylation enhanced PDHK1 kinase activity by promoting ATP and pyruvate dehydrogenase complex (PDC) binding. Functional PDC formed in mitochondria outside of the matrix in some cancer cells.

Expression of a mutant, nonfunctional form of PDHK1 in cancer cells led to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate and reduced tumor growth in xenograft nude mice.

“We and others have shown that PDHK is upregulated in several types of human cancer, and our findings demonstrate a new way that PDHK activity is enhanced in cancer cells,” said senior author Dr. Jing Chen, associate professor of hematology and medical oncology at Emory University School. “PDHK is a very attractive target for anticancer therapy because of its role in regulating cancer metabolism. We used FGFR1 as a platform to look at how metabolic enzymes are modified by oncogenic tyrosine kinases. We discovered that several oncogenic tyrosine kinases activate PDHK, and we found that many of those tyrosine kinases are found within mitochondria.”

The experimental drug dichloroacetate (DCA), which inactivates PDHK, is being evaluated in clinical trials while researchers continue to seek other, more potent inhibitors of PDHK.

Related Links:
Emory University



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: S-649266 has more robust antibacterial activity than established antibiotics against multidrug-resistant bacteria (Photo courtesy of Shionogi).

Novel Antibiotic Shows Potential for Broad Range of Infections

The emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating the infection caused by multi drug resistant (MDR) bacteria. In order to treat bacterial... Read more

Business

view channel

Collaboration of Mayo Clinic and IBM Cognitive Computer Devised to Improve Clinical Trial Research

The Mayo Clinic (Rochester, MN, USA) and IBM (Armonk, NY, USA) recently announced plans to pilot Watson, the IBM cognitive computer, to match patients more rapidly with suitable clinical trials. A proof-of-concept phase is currently ongoing, with the intent to introduce it into clinical use in early 2015.... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.