Forum for Science, Industry and Business

Aurora-A hinders tumor-suppressor to allow chemotherapy resistance

A protein abundantly found in treatment-resistant cancers holds an important tumor-suppressor out of the cell nucleus, where it would normally detect DNA damage and force defective cells to kill themselves, a team of scientists reports in the current Cancer Cell.

"Overexpression of Aurora Kinase-A in tumors has been correlated with resistance to DNA-damaging chemotherapy, but we haven't known how this occurs," said senior author Subrata Sen, Ph.D., professor in The University of Texas MD Anderson Cancer Center Department of Molecular Pathology.

"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," Sen said. Drugs that inhibit Aurora kinases are under development and some have advanced to cancer clinical trials.

Like p53, its better-known cousin, the tumor-suppressor p73 monitors DNA damage during cell division and orders apoptosis - programmed cell death - when it detects damage that can't be repaired. It's an ally of DNA-damaging chemotherapy such as cisplatin, which is designed to trigger apoptosis.

"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," Sen said. Inactivation of p53 is common in many types of solid tumors.

Sticking a phosphate group on p73 keeps it out of the nucleus

Having detected DNA damage, p73 works in the cell nucleus to activate genes that cause cell death.

Aurora-A is a kinase, a protein that regulates other proteins by attaching phosphate groups, consisting of one phosphorus atom connected to four oxygen atoms, at specific binding sites.

Mortalin ties phosphorylated p73 in cytoplasm

Sen and colleagues found that the protein mortalin binds to p73 that's been phosphorylated by Aurora-A, and plays a role moving p73 out to the cytoplasm and keeping it there. Mortalin has been implicated in tumor formation and immortalization.

In addition to DNA damage, p73 also regulates the mitotic spindle assembly checkpoint, which regulates a specific mechanism involved in the normal separation of chromosomes during cell division. The team found that Aurora-A phosphorylation of p73 also inactivates this checkpoint function.

They also found Aurora-A expressed at normal levels has a regular role to play in phosphorylating p73 in normal spindle assembly checkpoint function during cell division.

Aurora-A effect on p73 found in human pancreatic cancer

When they treated lung cancer cells 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.

The team analyzed p73 and Aurora-A in 114 samples of human pancreatic ductal adenocarcinoma at MD Anderson and found 51 (44.7 percent) had high Aurora-A expression and 37 of those had high levels of p73 in the cytoplasm. Of the 63 low-Aurora-A tumors, only 18 (28.6 percent) had high levels of p73 in the cytoplasm.

Inactivation of the DNA and spindle damage-induced cell death pathways make these pancreatic tumors resistant to chemotherapy and radiation, the researchers noted. Further analysis of p73 phosphorylation tumor profiles and sensitivities to chemotherapy and radiation would assist in the development of targeted therapies and combinations.

This research was funded by grants from the National Cancer Institute, including the MD Anderson Cancer Center Support Grant, and an NCI Early Detection Research Network award.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in "Best Hospitals," a survey published annually in U.S. News & World Report.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...