Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH MEDIA
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC

Overabundant Protein Kinase Found Connected to Chemotherapy-Resistant Cancer Cells

By BiotechDaily International staff writers
Posted on 06 Mar 2012
A molecular signaling pathway underlying the correlation of Aurora Kinase-A overexpression in human tumors with resistance to chemotherapy has been discovered.

In treatment-resistant cancers, this abnormally abundant protein kinase was found to prevent an important tumor-suppressor, p73, from entering the cell nucleus, where it would normally detect DNA damage and activate genes that force defective cells to undergo apoptosis. Like the better known p53, the tumor-suppressor p73 monitors DNA damage during cell division and orders apoptosis when it detects damage that cannot be repaired.

Inactivation of p53 is known to be common in many types of solid tumors. "The role of p73 in the maintenance of genomic stability has been better recognized in recent years and this tumor suppressor is believed to be functionally more important in cells that lack p53," said Subrata Sen, PhD, professor in the Department of Molecular Pathology at The University of Texas MD Anderson Cancer Center (Houston, TX, USA).

In a study reported in the February 14, 2012, issue of the journal Cancer Cell, senior author Sen and colleagues found that site-specific phosphorylation of p73 by Aurora Kinase-A (Aurora-A) leads to (a) loss of p73 ability to bind to DNA and to transactivate its target genes and (b) locking of p73 outside the nucleus, in the cell cytoplasm.

The chaperon protein Mortalin, which has been implicated in tumor formation and immortalization, was found to play a role in keeping Aurora-A phosphorylated p73 in the cytoplasm as well as in moving it out of the nucleus. Experiments in the study showed that lung, breast, and pancreatic cancer cells overexpressing Aurora-A have p73 evenly distributed in the nucleus and cytoplasm, but when treated with an Aurora-A inhibitor, p73 is found mainly in the nucleus. The team also analyzed 114 samples of human pancreatic ductal adenocarcinoma.

In addition, when lung cancer cells overexpressing Aurora-A were treated with cisplatin, cells with phosphorylated p73 were least sensitive to cell death caused by the chemotherapy. In the absence of Aurora-A overexpression, cells were more sensitive to cisplatin treatment.

In another aspect of the study, the investigators found that Aurora-A expressed at normal levels has a regular role to play in phosphorylating p73 in normal mitotic spindle assembly checkpoint function during cell division but that overabundant Aurora-A phosphorylation of p73 leads to dissociation, and thereby malfunction, of the spindle assembly checkpoint complex.

"Our discovery that Aurora A blocks the proper functioning of the tumor-suppressor p73 is a step toward understanding and addressing chemotherapy resistance with more effective treatment combinations," said Prof. Sen.

Related Links:
The University of Texas MD Anderson Cancer Center





Channels

Genomics/Proteomics

view channel
Image: Many molecular biology studies begin with purified DNA and RNA extracted from complex environments such as the human gut (Photo courtesy of Los Alamos [US] National Laboratory).

New Metagenomics Analysis Tool Reduces False Discovery Rates

Genomic researchers recently described a novel new tool for analyzing the complex data generated during DNA screens of mixed populations of organisms such as the human gut microbiome. DNA screening... Read more

Drug Discovery

view channel
Image: Wafers like the one shown here are used to create “organ-on-a-chip” devices to model human tissue (Photo courtesy of Dr. Anurag Mathur, University of California, Berkeley).

Human Heart-on-a-Chip Cultures May Replace Animal Models for Drug Development and Safety Screening

Human heart cells growing in an easily monitored silicon chip culture system may one day replace animal-based model systems for drug development and safety screening. Drug discovery and development... Read more

Biochemistry

view channel
Image:  Model depiction of a novel cellular mechanism by which regulation of cryptochromes Cry1 and Cry2 enables coordination of a protective transcriptional response to DNA damage caused by genotoxic stress (Photo courtesy of the journal eLife, March 2015, Papp SJ, Huber AL, et al.).

Two Proteins Critical for Circadian Cycles Protect Cells from Mutations

Scientists have discovered that two proteins critical for maintaining healthy day-night cycles also have an unexpected role in DNA repair and protecting cells against genetic mutations that could lead... Read more

Business

view channel

“Softer” Mass Spec Techniques Gain Advantage in Biomarker Discovery

Two mass spectrometry (MS) technologies, MALDI and DESI, are increasing in applications as their effectiveness is established, according to Kalorama Information (New York, NY, USA) in its report “Proteomics Markets for Research and IVD Applications (Mass Spectrometry, Chromatography, Microarrays, Electrophoresis, Immunoassays,... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.