Over-expression of Aurora Kinase-A correlates with resistance to DNA-damaging chemotherapy
Scientists find molecular path blocking the proper function of tumour-suppressor p73
- Date : 08 Mar 2012
- Topic : Anticancer agents & Biologic therapy
Over-expression of Aurora Kinase-A in tumours has been correlated with resistance to DNA-damaging chemotherapy, but scientists haven't known how this occurs. Discovery reported in the current Cancer Cell by a team of researchers from The University of Texas MD Anderson Cancer Centre, that Aurora A blocks the proper functioning of the tumour-suppressor p73 is a step toward understanding and addressing chemotherapy resistance. Drugs that inhibit Aurora kinases are under development and some have advanced to cancer clinical trials.
Like p53, its better-known cousin, the tumour-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.
According to senior author of the study Subrata Sen, PhD, professor in The University of Texas MD Anderson Cancer Centre Department of Molecular Pathology, the role of p73 in the maintenance of genomic stability has been better recognized in recent years and this tumour suppressor is believed to be functionally more important in cells than lack p53. Inactivation of p53 is common in many types of solid tumours.
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 p73 loses its ability to bind to DNA and to transactivate its target genes and p73 gets locked outside the nucleus in the cell's cytoplasm.
The researchers found lung 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. They repeated this experiment with similar results in breast and pancreatic cancer cell lines in which Aurora-A is overexpressed.
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 tumour 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 researchers 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 analysed p73 and Aurora-A in 114 samples of human pancreatic ductal adenocarcinoma at MD Anderson and found 51 (44.7%) had high Aurora-A expression and 37 of those had high levels of p73 in the cytoplasm. Of the 63 low-Aurora-A tumours, only 18 (28.6%) had high levels of p73 in the cytoplasm.
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