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.Sen and colleagues found that Aurora-A phosphorylates p73 at a specific site and when that happens:
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.Sen and colleagues, as well as other research teams, previously found that Aurora-A phosphorylation also inhibits p53-induced cell death after chemotherapy or radiation treatment. The new findings suggest both p53 and p73 DNA damage responses are blocked by Aurora-A phosphorylation after they interact with mortalin and are moved to the cytoplasm.
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!
Bolstering fat cells offers potential new leukemia treatment
17.10.2017 | McMaster University
Ocean atmosphere rife with microbes
17.10.2017 | King Abdullah University of Science & Technology (KAUST)
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
17.10.2017 | Life Sciences
17.10.2017 | Life Sciences
17.10.2017 | Earth Sciences