Figure1. Aurora kinase signaling pathway.
Aurora kinase overview
Aurora kinase is an important class of serine/threonine kinases responsible for the regulation of cell mitosis. In different model organisms, the structural and functional parts of members of the Aurora kinase family are highly conserved. In recent years, with the deepening of research on Aurora kinase, people have gradually recognized the important functions of Aurora kinase in cell mitosis and tumor formation. In cell mitosis, Aurora kinases are involved in many events such as centrosome maturation, spindle assembly and maintenance, chromosome segregation, and cytokinesis. Abnormally expressed aurora kinases tend to cause many abnormalities in the process of mitosis. In addition, Aurora kinase is involved in the process of tumor formation, and it has been found that some small molecules that target the aurora kinases have significant anti-cancer effects.
Aurora kinase family
Aurora kinase was first discovered in Drosophila mutants and was named for its abnormal spindle morphology like the Northern Lights. The human genome contains three aurora kinase members: aurora a, aurora b, and aurora c. These three homologous aurora kinases contain a conserved C-terminal catalytic domain and an N-terminal domain of varying lengths, all of which have different localization and function during mitosis. The aurora a gene is located on chromosome 20q13. From the S phase of the cell to the end of mitosis, Aurora A is localized to the centrosome. In addition, Aurora A is also distributed on the spindle microtubes. Aurora A plays an important role in mitosis. It regulates centrosome separation by phosphorylation of Eg5 in the early and middle stages. Deletion of Aurora-A or inhibition of its activity can cause centrosome separation failure, which ultimately leads to the appearance of a monopolar spindle. The maturation of the centrosome relies on centrosomin, NDEL1, T cell activation-associated protein (LAT), and transcription-associated acid coiled protein (TACC), which regulates the localization and function of these proteins. Aurora A has been shown to be essential for centrosome maturation in nematodes, fruit flies, and human cells. Ran GTP is a small GTPase that promotes the release of microtubule assembly factors TPX2, Numa, and NuSAP by binding to the input protein-β. The released TPX2 binds to Aurora A and is phosphorylated, assisting Aurora A to locate on the microtube near the pole. In mammalian cells, interference with Aurora A or TPX2 can cause the formation of a multipolar spindle, indicating that the interaction of TPX2 with Aurora A is a necessary condition for the formation of a bipolar spindle. In addition to its role in centrosome separation, maturation, and spindle assembly, Aurora A also promotes cell entry into the dividing phase via Cyclin-B/Cdk1. Inhibition of Aurora A activity by RNAi delays cell entry into the mitosis phase, whereas overexpression can impair spindle checkpoint function and inhibit cytokinesis. The coding gene of Aurora B is located on chromosome 17p13. It is a chromosomal passenger protein that forms a chromosomal passenger protein complex with other three chromosomal passenger proteins, INCENP, borealin, and survin, in mammalian cells. In the early stage of mitosis, Aurora B is distributed along the chromosome arm and then aggregates on the centromere of the chromosome and remains until the middle of the division. After splitting into the late stage, Aurora B migrates from the centromere to the middle region of the central spindle and the cell cortex of the dividing groove. In cytokinesis, Aurora B further aggregates into the intermediate. Aurora B can promote chromatin condensation. Studies have shown that Aurora B inhibitors can increase the probability of chromosome segregation disorders, indicating that Aurora B plays an important role in chromosome orientation and separation. The spindle assembly checkpoint is primarily used to monitor the behavior of mitotic metaphase chromosomes. Once the kinetochore and microtubules lose connection or there is no tension between the two, the checkpoint can be activated, preventing the cells from entering the late stages of division. Aurora B can regulate this process by acting on checkpoint proteins (Mps1, Mad, Bud). Aurora B is also one of the essential kinases for normal cytokinesis, which regulates various stages of cytokinesis through different substrate molecules. The aurora c gene is located on chromosome 19q13 and is highly expressed in mammalian testes. It has been thought that Aurora C is strictly localized in the central body and involved in meiotic spindle formation in the later stages and during cytokinesis. However, in recent years, many experiments have shown that, like Aurora B, Aurora C is also activated by INCENP. Overexpression of Aurora C and INCENP caused an increase in phosphorylation of the substrate histone H3 of Aurora B, indicating that Aurora C is also a chromosomal passenger protein and functions similarly to Aurora B. However, Aurora C has only been detected in the testes, and the expression of Aurora C has not been detected in other somatic cells.
Aurora kinase signaling pathway
Aurora kinase signaling pathway cascade
The aurora a gene is in an amplifying active chromosomal segment that has been identified as a proto-oncogene. Many studies have found amplification and overexpression of aurora A in various tumor cells such as pancreatic cancer, liver cancer, lung cancer, prostate cancer, bone cancer and ovarian cancer. Overexpression of Aurora A in murine NIH 3T3 cells causes an abnormal number of centrosomes and causes cancerous cells. However, overexpression of Aurora A in primary cells does not cause cancerous cells, suggesting that Aurora A is involved in tumorigenesis and is dependent on other signaling pathways. Increased Ras/Raf/MEK1/ERK/MAPK kinase pathways enhance cell response to growth signals during cell carcinogenesis. Recent studies have found that Aurora A is a downstream target of MAPK and ERK1/2 in pancreatic cancer. The interaction between Aurora A and the tumor suppressor gene p53 is closely related to tumorigenesis. Aurora A directly phosphorylates P53 to regulate its stability and transcriptional process. Two Aurora A phosphorylation sites have been found in P53: Ser315 phosphorylation can enhance the interaction of p53 with Mdm2 and thereby promoting the ubiquitination and degradation of p53 protein; Ser215 phosphorylation of p53 can be released in conjunction with DNA, and in turn, inhibits its downstream target genes. Gadd45a p53 may mediate the binding of Aurora A and inactivates of p53. It has been reported that over-expressed Aurora A causes tumor cells to be resistant to paclitaxel. Tumor cells activate NF-κB during chemotherapy or radiation therapy, although activation of NF-κB promotes tumor cell apoptosis under certain conditions. Sustained activation of NF-κB causes tumor cell resistance, and Aurora A activates the NF-κB signaling pathway by promoting phosphorylation of NF-κB to promote cancer process. In addition, studies have found that Aurora A overexpression promotes tumor cell migration and drug resistance by activating the Akt signaling pathway. aurora B is located on chromosome 17p13, which is not an active segment, and it is not a proto-oncogene. Although the role of Aurora B in tumorigenesis is less clear, it is as highly expressed in a variety of tumor cells as Aurora A. Overexpression of Aurora B can also cause genomic instability in cells. For example, aurora B overexpression in CHO cells produces aneuploidy and increases tumor invasiveness.
Pathway regulation and clinical research
The specific mechanism by which Aurora kinase participates in tumorigenesis remains unclear, but its relevance to tumors has been recognized. A number of studies have demonstrated that Aurora kinase is highly expressed in many tumor tissues, while Aurora kinases are only activated in mitosis and their expression in non-proliferating cells is low. In the human body, most normal cells do not proliferate at a rapid rate. Therefore, inhibitors targeting Aurora kinase have a greater advantage than other non-specific cytotoxic drugs, which is also an important reason for them to act as potential therapeutic targets for cancer. In summary, Aurora kinase has been listed as an anti-tumor target and research hotspot with important development prospects, and more and more Aurora kinase inhibitors have attracted people's attention. To date, more than 30 Aurora kinase inhibitors have been introduced into clinical trials as potential anti-cancer drugs such as ZM447439, PHA739358, CYC116, VX680, AT9283, PF03814375, GSK1070916, and MLN8054. These compounds exhibit good antitumor activity both in vitro and in vivo. ZM447439 is the first aurora kinase inhibitor. It can increase the number of apoptotic cells and the formation of p53-dependent polyploids. Earlier in vitro experiments showed that ZM447439 inhibited the activity of Aurora A and Aurora B simultaneously, with an IC50 of approximately 100 nmol/L. However, recent experiments have shown that it acts mainly by inhibiting Aurora B in the body, and therefore, the drug is a selective Aurora B inhibitor. According to reports, ZM447439 has no effect on several other key cell cycle regulator activities. Although the study of ZM447439 has been discontinued before clinical use, it is still widely used in the research of the initial stage of Aurora kinase drug target validation. Hesperadin is the first Aurora B inhibitor that inhibits histone H3 phosphorylation. In vitro experiments have shown that hesperadin causes chromosome segregation and abnormal cytokinesis, which eventually leads to the appearance of polyploids. Currently, hesperadin is in Phase I clinical trials. MLN8237 is a novel aurora kinase inhibitor with a 200-fold selective inhibition of Aurora A and an IC50 of 1 nmol/L. It inhibits the growth of various tumor cells such as HCT116, PC3, SK-OV3, and LY3 in vitro. The results of phase I clinical trials showed that the lethal effect of MLN8237 was smaller than that of MLN8054, and there were also adverse reactions such as neutropenia, mucositis and alopecia. Phase II trials for lung cancer, breast cancer, etc. are currently underway.
Goldenson B, Crispino J D. The aurora kinases in cell cycle and leukemia. Oncogene. 2015, 34(5):537-45.
Mehra R, Serebriiskii I G, Burtness B, et al. Aurora kinases in head and neck cancer. Lancet Oncology. 2013, 14(10)e425-e435.
Baldini E, Tuccilli C, Prinzi N, et al. Deregulated expression of Aurora kinases is not a prognostic biomarker in papillary thyroid cancer patients. Plos One. 2014, 10(3).
Arlotbonnemains Y, Baldini E, Martin B, et al. Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines. Endocrine-related cancer. 2008, 15(2):559.
Marxer M, Ma H T, Man W Y, et al. p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases. Oncogene. 2013, 33(27):3550-60.
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