Chromosomal instability (CIN) is defined as the perpetual missegregation of whole chromosomes during mitosis and represents a hallmark of human cancer. However, the mechanisms causing CIN and its consequences on tumor growth are largely unknown. We identify an increase in microtubule plus end assembly rates as a fundamental trigger for CIN in CRC cells. This trigger is mediated by overexpression of the oncogene AURKA or by loss of the tumor suppressor gene CHK2, a genetic constitution found in 73% of human colorectal cancers. Increased microtubule assembly rates are associated with transient abnormalities in mitotic spindle geometry promoting the generation of lagging chromosomes and resulting in CIN. Reconstitution of proper microtubule assembly rates by chemical or genetic means suppresses CIN and thereby, unexpectedly, accelerates tumor growth in vitro and in vivo. Thus, we identify a fundamental mechanism triggering CIN in cancer cells and reveal its adverse consequence on tumor growth.
Chromosomal instability (CIN) is a major hallmark of human cancer and might contribute to tumorigenesis. Genes required for the normal progression of mitosis represent potential CIN genes and, as such, are important tumour suppressors. The Chk2 kinase and its downstream targets p53 and Brca1 are tumour suppressors that have been functionally linked to the DNA damage response pathway. Here, we report a function of Chk2, independent of p53 and DNA damage, that is required for proper progression of mitosis, and for the maintenance of chromosomal stability in human somatic cells. Depletion of Chk2 or abrogation of its kinase activity causes abnormal mitotic spindle assembly associated with a delay in mitosis, which promotes the generation of lagging chromosomes, chromosome missegregation and CIN, while still allowing survival and growth. Furthermore, we have identified Brca1 as a mitotic target of the Chk2 kinase in the absence of DNA damage. Accordingly, loss of BRCA1 or its Chk2-mediated phosphorylation leads to spindle formation defects and CIN. Thus, the CHK2-BRCA1 tumour suppressor pathway is required for chromosomal stability, which might contribute to their tumour suppressor function.
CHK2 is a multiorgan tumor susceptibility gene that encodes for a serine/threonine protein kinase involved in the response to cellular DNA damage. After ATM-mediated phosphorylation, the activated Chk2 kinase can act as a signal transducer and phosphorylate a variety of substrates, including the Cdc25 phosphatases, p53, PML, E2F-1, and Brca1, which has been associated with halting the cell cycle, the initiation of DNA repair, and the induction of apoptosis after DNA damage. In addition, recent work has revealed another, DNA-damage-independent function of Chk2 during mitosis that is required for proper mitotic spindle assembly and maintenance of chromosomal stability. This novel role involves a mitotic phosphorylation of the tumor suppressor Brca1 by the Chk2 kinase. On the basis of its role during DNA damage response, Chk2 has been suggested as an anticancer therapy target, but given its recently discovered new function and its role as a tumor suppressor, it is questionable whether inhibition of Chk2 is indeed beneficial for anticancer treatment. However, investigators may be able to exploit the loss of CHK2 in human tumors to develop novel therapies based on synthetic lethal interactions.
The mitotic Aurora kinases, including Aurora-A and Aurora-B, are attractive novel targets for anticancer therapy, and inhibitory drugs have been developed that are currently undergoing clinical trials. However, the molecular mechanisms how these drugs induce tumor cell death are poorly understood. We have addressed this question by comparing the requirements for an efficient induction of apoptosis in response to MLN8054, a selective inhibitor of Aurora-A, and the selective Aurora-B inhibitor ZM44-7439 in human colon carcinoma cells. By using various isogenic knockout as well as inducible colon carcinoma cell lines, we found that treatment with MLN8054 induces defects in mitotic spindle assembly, which causes a transient spindle checkpoint-dependent mitotic arrest. This cell cycle arrest is not maintained due to the activity of MLN8054 to override the spindle checkpoint. Subsequently, MLN8054-treated cells exit from mitosis and activate a p53-dependent postmitotic G 1 checkpoint, which subsequently induces p21 and Bax, leading to G 1 arrest followed by the induction of apoptosis. In contrast, inhibition of Aurora-B by ZM447439 also interferes with normal chromosome alignment during mitosis and overrides the mitotic spindle checkpoint but allows a subsequent endoreduplication, although ZM447439 potently activates the p53-dependent postmitotic G 1 checkpoint. Moreover, the ZM447439-induced endoreduplication is a prerequisite for the efficiency of the drug. Thus, our results obtained in human colon carcinoma cells indicate that although both Aurora kinase inhibitors are potent inducers of tumor cell death, the pathways leading to the induction of apoptosis in response to these drugs are distinct.
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