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.
The University of Texas MD Anderson Cancer Center