AURKA gene amplification and/or over-expression is a frequent finding in several malignancies including breast, colon, pancreas, ovaries, bladder, liver, and gastric cancers (19
). AURKA over-expression can occur because of gene amplification, transcriptional induction or post-translational stabilization (22
). Interest in AURKA intensified after a series of preclinical studies demonstrated the oncogenic potential of AURKA activation resulting in the in vitro
and in vivo
transformation of rodent fibroblast cells and the formation of multipolar mitotic spindles inducing genome instability (23
) establishing AURKA as a bona fide oncogene (). AURKA over-expression has been reported to be significantly associated with a higher grade of tumor and a poor prognosis (24
). Aneuploidy is a good marker of tumor progression and prognosis caused due to chromosomal instability, the most frequent genomic damage that occurs during cancer development. In gastric carcinoma and in papillary thyroid carcinoma aneuploidy is a marker of metastasis (25
) and in many malignancies aneuploidy is associated with a poor outcome (27
). A correlation between AURKA over-expression and aneuploidy exists in gastric cancer; clinical samples with AURKA amplification and over-expression showed aneuploidy and poor prognosis (20
). AURKA plays an important role in centrosome maturation, and numerous centrosomal abnormalities are observed in AURKA-deficient cells. Centrosomal anomalies have been reported to arise at early stages of tumor formation and to expand concomitant with tumor progression (28
) a process in agreement with the AURKA expression profile pattern which increases from early to late stages of tumor. Although no direct link has been found between AURKA overexpression and centrosome abnormalities in cancer, AURKA over-expression, centrosome amplification and aneuploidy are always associated. Centrosomal abnormalities lead to bipolar mitotic spindle defects, chromosomal segregation deficiency and aneuploidy. Centrosomal aberrations are found in brain (29
), breast (30
), lung, colon and prostrate tumors (29
). Furthermore, centrosome aberrations lead to aneuploidy, suggesting that AURKA over-expression is responsible for centrosome amplification, and thus, participates in tumorigenesis.
Overview of the different effects that are observed upon over-expression and/or amplification of AURKA.
AURKA binds and phosphorylates the breast cancer associated gene product, BRAC1, in vitro
and in vivo
to regulate its function (31
). It is reported that ovarian and breast epithelial carcinomas play a role in the regulation of human telomerase reverse transcriptase mRNA levels through c-Myc (32
). AURKA has also been reported to override the spindle checkpoint activated by paclitaxel (Taxol) and nocodazole (33
). These defects might contribute to transformation.
AURKA interacts with the p53 pathway at multiple levels, suggesting that these proteins form a part of an integrated functional network. AURKA interferes with p53 suppressor function by at least two mechanisms: it directly phosphorylates p53 at Ser315 facilitating MDM-2 mediated degradation of p53 in cancer cells (34
), and it also phosphorylates p53 at Ser215 to inactivate its transcriptional activity (35
). In addition to these two mechanisms, our work suggests regulation of p53 through AKT/MDM-2 axis in gastric cancer cells (36
). We also reported that AURKA over-expression suppresses TAp73 in p53 deficient cancer cells (37
). TAp73, a p53 family, member has significant homology with p53 and plays an essential role in apoptosis induced by cytotoxic agents (38
). The tumor suppressor proteins p53 and p73 can activate genetic programs that halt cell proliferation transiently (G1 and G2 cell cycle arrest) or permanently (senescence) or eliminate the cell altogether (apoptosis). Regulation of p53 and p73 by AURKA over-expression can lead to suppression of apoptosis of tumor cells. AKT is a major pro-proliferative serine/threonine kinase that promotes cell survival in a variety of cell types and prevents apoptosis induced by various apoptotic stimuli (39
). We (36
), and others (40
), have reported that AURKA up-regulates AKT phosphorylation at Ser473. We reported the regulation of GSK-3ß and ß-catenin (41
) by AURKA over-expression in gastric cancer cells. A schematic overview of possible AURKA interaction is shown in .
Figure 3 Schematic representation of AURKA interactions. AURKA over-expression inhibits p53 family members and suppresses apoptosis and cell cycle arrest. AURKA interacts directly with p53 by phosphorylating it at Ser215 (34) and 315 (35) causing its degradation (more ...)