Targeting a kinetochore-associated motor protein to kill cancer cells.

Abstract

Tumors are characterized by excessive proliferation and, therefore, chemotherapeutics that target proteins involved in tumor cell division can be effective anticancer agents. However, as many of these proteins are involved in core mechanisms in dividing and nondividing cells, these therapeutic agents do not selectively kill tumor cells and their efficacy is limited by general toxicity. As new therapeutics that target proteins involved in these core processes are developed, the likelihood increases of identifying a protein that cancer cells depend on more than normal cells. Wood et al. report the discovery and characterization of an inhibitor of a mitotic motor protein, centromere-associated protein-E (CENP-E, kinesin-7) (1). This inhibitor for a protein whose functions are limited to cell division has the potential to lead to improved cancer chemotherapies. Currently used antimitotic therapeutics target the cytoskeletal protein tubulin, which polymerizes to form microtubules (2). During cell division, segregation of chromosomes requires a microtubule-based bipolar spindle. Only after all chromosome pairs have been attached to the opposite ends of the bipolar spindle through microtubules, the spindle assembly checkpoint is satisfied, chromosomes are separated, and the cell cycle progresses. When normal tubulin polymerization dynamics are disrupted, proper chromosome-spindle attachments are not established, and the cell cycle is blocked by the checkpoint. Through poorly understood mechanisms, this cell-cycle arrest can lead to cell death (3). However, microtubules have essential roles in other cellular processes, such as neuronal transport. Therefore, the use of tubulin-targeting antimitotic agents is associated with side effects, including neurotoxicity. A decade ago, a small-molecule inhibitor, monastrol, was reported for … 1To whom correspondence should be addressed. E-mail: kapoor{at}rockefeller.edu.