Functional Significance of Aurora Kinases–p53 Protein Family Interactions in Cancer

Abstract

Aurora kinases play critical roles in regulating spindle assembly, chromosome segregation, and cytokinesis to ensure faithful segregation of chromosomes during mitotic cell division cycle. Molecular and cell biological studies have revealed that Aurora kinases, at physiological levels, orchestrate complex sequential cellular processes at distinct subcellular locations through functional interactions with its various substrates. Aberrant expression of Aurora kinases, on the other hand, cause defects in mitotic spindle assembly, checkpoint response activation, and chromosome segregation leading to chromosomal instability. Elevated expression of Aurora kinases correlating with chromosomal instability is frequently detected in human cancers. Recent genomic profiling of about 3000 human cancer tissue specimens to identify various oncogenic signatures in The Cancer Genome Atlas project has reported that recurrent amplification and overexpression of Aurora kinase-A characterize distinct subsets of human tumors across multiple cancer types. Besides the well-characterized canonical pathway interactions of Aurora kinases in regulating assembly of the mitotic apparatus and chromosome segregation, growing evidence also supports the notion that deregulated expression of Aurora kinases in non-canonical pathways drive transformation and genomic instability by antagonizing tumor suppressor and exacerbating oncogenic signaling through direct interactions with critical proteins. Aberrant expression of the Aurora kinases–p53 protein family signaling axes appears to be critical in the abrogation of p53 protein family mediated tumor suppressor pathways frequently deregulated during oncogenic transformation process. Recent findings reveal the existence of feedback regulatory loops in mRNA expression and protein stability of these protein families and their consequences on downstream effectors involved in diverse physiological functions, such as mitotic progression, checkpoint response pathways, as well as self-renewal and pluripotency in embryonic stem cells. While these investigations have focused on the functional consequences of Aurora kinase protein family interactions with wild-type p53 family proteins, those involving Aurora kinases and mutant p53 remain to be elucidated. This article presents a comprehensive review of studies on Aurora kinases–p53 protein family interactions along with a prospective view on the possible functional consequences of Aurora kinase–mutant p53 signaling pathways in tumor cells. Additionally, we also discuss therapeutic implications of these findings in Aurora kinases overexpressing subsets of human tumors.

Aurora kinase A as a possible marker for endocrine resistance in early estrogen receptor positive breast cancer

“…Several studies have shown that the mitotic Aurora kinase A is a poor prognostic marker in breast cancer [9][10][11]17,18,20], and we found borderline significance for reduced OS in this group of breast cancer patients with early breast cancer treated with adjuvant endocrine therapy. Aurora A is not only a cell cycle regulator but is also involved in many different signaling cross-talks within the cells [5][6][7], including activation of the ER via phosphorylation [12]. Our finding in this study which included 980 early breast cancer patients showed that Aurora A did not show significance as prognostic or predictive marker for response to tamoxifen or to letrozole.…”

“…Studies of cell culture models mimicking ER positive breast cancer resistant to the antiestrogens tamoxifen and fulvestrant and also to aromatase inhibitors have disclosed that Aurora kinases are important for growth of both antiestrogen and aromatase inhibitor resistant breast cancer cells [2][3][4]. Aurora kinases (A, B and C) are key regulators of mitosis and multiple signaling pathways [5,6]. Gene amplification and protein overexpression of Aurora kinases have been found in both hematologic malignancies and solid tumors and deregulation of Aurora kinases has been linked to tumorigenesis [7].…”

Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma

“…The Aurora kinase family, and in particular Aurora A, is required for multiple mitotic events and its aberrant expression is related to tumorigenesis. 22 To date, a number of inhibitors targeting Aurora A, B and pan-Aurora kinase have been approved by the FDA for cancer management, such as for ovarian cancer and acute myelogenous leukemia (AML). 23 Another commonly down-regulated gene is HMMR (Hyaluronan-mediated motility receptor), also known as the receptor for hyaluronan-mediated motility (RHAMM).…”

Targeting oncogenic Myc as a strategy for cancer treatment

“… 47 AURKA contributes to tumorigenesis through interactions with P53 and Myc. 48 – 50 Recently, Otto et al 14 showed that Aurora A and N-Myc acted as oncogenic partners in neuroblastomas. AURKA forms a complex with N-Myc, which protects N-Myc from FBW7-mediated proteasomal degradation.…”