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

Drug Discovery

view channel
Image: Molecular model of the protein Saposin C (Photo courtesy of Wikimedia Commons).

Nanovesicles Kill Human Lung Cancer Cells in Culture and in a Mouse Xenograft Model

Nanovesicles assembled from the protein Saposin C (SapC) and the phospholipid dioleoylphosphatidylserine (DOPS) were shown to be potent inhibitors of lung cancer cells in culture and in a mouse xenograft model.... Read more

Biochemistry

view channel

Possible New Target Found for Treating Brain Inflammation

Scientists have identified an enzyme that produces a class of inflammatory lipid molecules in the brain. Abnormally high levels of these molecules appear to cause a rare inherited eurodegenerative disorder, and that disorder now may be treatable if researchers can develop suitable drug candidates that suppress this enzyme.... Read more

Lab Technologies

view channel
Image: The FLUOVIEW FVMPE-RS Gantry microscope (Photo courtesy of Olympus).

New Multiphoton Laser Scanning Microscope Configurations Expand Research Potential

Two new configurations of a state-of-the-art multiphoton laser scanning microscope extend the usefulness of the instrument for examining rapidly occurring biological events and for obtaining images from... Read more

Business

view channel

Roche Acquires Signature Diagnostics to Advance Translational Research

Roche (Basel, Switzerland) will advance translational research for next generation sequencing (NGS) diagnostics by leveraging the unique expertise of Signature Diagnostics AG (Potsdam, Germany) in biobanks and development of novel NGS diagnostic assays. Signature Diagnostics is a privately held translational oncology... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.