Kitagawa R: The impaired SAC activity and sensitivity to antimitotic agents



We are also studying the SAC pathway for its role in determining drug sensitivity of cancer cells.  The common outcome of treatment with antimitotic agents is chronic mitotic arrest, which in turn causes chronic activation of the SAC pathway. Cells arrested in mitosis from sustained SAC activity eventually become adapted, owing to which they skip cytokinesis and enter the G1 phase. Adapted cells could trigger the apoptotic pathway, senesce, or continue to divide. Continuous division might be an undesirable outcome, potentially generating cancer cells that are aneuploid and resistant to antimitotic agents. Experimental data have suggested that the frequency of cells surviving drug treatment increases when the SAC is compromised. However, the relationship between the duration of mitotic delay and cell survival is unknown. It is therefore important to establish the molecular relationship between the SAC pathway and cell death or survival pathways to understand the molecular basis of drug sensitivity of cancer cells. We will study the role of the SAC pathway in activating the cell death pathway in response to chemical or mutational disruption of microtubules, using C. elegans strains in which nonessential SAC genes have been deleted. C. elegans is a useful model because some conserved SAC components are dispensable, and we can analyze the cellular response to antimitotic agents in the absence of functional SAC. Also, the cell death pathway of C. elegans has molecular components similar to those of the apoptotic pathway in mammals.


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