Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING
PZ HTL SA
GLOBETECH PUBLISHING

Pancreatic Cancer Cells Vulnerable to Glutamine Pathway Inhibitors

By BiotechDaily International staff writers
Posted on 10 Apr 2013
Pancreatic cancer cells utilize the amino acid glutamine to fuel their metabolism and are dependent on a single molecular pathway that may be susceptible to pharmaceutical inhibition.

Investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) reported in the March 27, 2013, online edition of the journal Nature that they had identified a noncanonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that was required for tumor growth. While most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle (Kreb's cycle), PDAC was shown to rely on a distinct pathway in which glutamine-derived aspartate was transported into the cytoplasm where it was converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate was converted into malate and then pyruvate, increasing the NADPH/NADP+ ratio, which could then maintain the cellular redox state.

PDAC cells were strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway led to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions resulted in a pronounced suppression of PDAC growth in vitro and in vivo.

Reprogramming of glutamine metabolism by PDAC was found to be mediated by the KRAS oncogene. The protein product of the normal KRAS (Kirsten rat sarcoma viral oncogene) gene performs an essential function in normal tissue signaling, and its mutation is an essential step in the development of many cancers. A single amino acid substitution is responsible for the activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma.

“Pancreatic cancer cells have painted themselves into a metabolic bottleneck,” said senior author Dr. Alec Kimmelman, assistant professor of radiation oncology at the Dana-Farber Cancer Institute. “If you suppress any enzyme in that pathway, the cancer cells cannot effectively compensate and they can no longer grow. We do not have a drug to do this in humans, but we are working on inhibitors of enzymes in the glutamine pathway.”

Related Links:

Dana-Farber Cancer Institute



Channels

Drug Discovery

view channel
Image: Chitosan is derived from the shells of shrimp and other sea crustaceans, including Alaskan pink shrimp, pictured here (Photo courtesy of NOAA - [US] National Oceanic and Atmospheric Administration).

Chitosan Treatment Clears the Way for Antibiotics to Eliminate Recurrent Urinary Tract Infections

Recurrent urinary tract infection was successfully resolved in a mouse model by treatment with the exfoliant chitosan followed by a round of antibiotics. Bacterial urinary tract infection (UTI), most... Read more

Biochemistry

view channel

Mitochondrial Cause of Aging Can Be Reversed

Researchers have found a cause of aging in lab animals that can be reversed, possibly providing an avenue for new treatments for age-related diseases including type 2 diabetes, cancer, muscle wasting, and inflammatory diseases. The researchers plan to begin human trials late 2014. The study, which was published December... Read more

Therapeutics

view channel

Cytokine Identified That Causes Mucositis in Cancer Therapy Patients

The action of the cytokine interleukin 1-beta (IL-1beta) has been found to underlie the onset of mucositis, a common, severe side effect of chemotherapy and irradiation of cancer patients. Mucositis occurs as a result of cell death in reaction to chemo- or radiotherapy. The mucosal lining of the mouth becomes thin, may... Read more

Business

view channel

Analytical Sciences Trade Fair Declared a Rousing Success

Organizers of this year's 24th "analytica" biosciences trade fair have reported significant increases in both the number of visitors and exhibitors compared to the 2012 event. The analytica trade fair for laboratory technology, analysis, and biotechnology has been held at the Munich (Germany) Trade Fair Center every... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.