Cells are cautious about passing genetic information onto their successors. The delicate process has built-in safeguards that stop a cell in its tracks if something goes awry.
Most cancer drugs take advantage of one of these defenses. When DNA is parceled out during cell division, or mitosis, arrays of microtubules extend like fingers from opposite sides of the cell to separate neatly lined up pairs of chromosomes. It is this pose—symmetric filaments arcing toward the center of the cell—that forms the mitotic spindle, a transient structure of the cell skeleton. The spindle mechanism is a common anticancer target. A natural brake called the spindle assembly checkpoint (SAC) routinely shuts down the division of cells whose chromosomes are improperly arranged, leading to cell death. Chemotherapeutic agents that activate the checkpoint can have the same effect. Since tumor cells divide rapidly, they are particularly vulnerable to the therapeutic activation of the SAC.
In the Oct. 6 issue of Cancer Cell, Hsiao-Chun Huang, a graduate student in the program of systems biology, and colleagues in the laboratory of Timothy Mitchison, the Hasib Sabbagh professor of systems biology, propose that the SAC is not the best target for anticancer therapeutics. A consequence of SAC activation—being stuck in division mode for a prolonged period—is what actually kills tumor cells. So the researchers looked for ways to cut out the middleman. In their study, they report they may have found one: knocking down a particular molecule to effectively lock the exit from cell division.
Despite years of research, it is unknown how attacks on the spindle kill dividing cells. “We absolutely can’t draw a diagram all the way from poisoning the microtubules to the cancer cell dying,” said Mitchison. Huang learned one important clue, however: the SAC does not directly trigger cell death in mitosis. In fact, mitotic arrest can lead to cell death even when the SAC is out of commission. This finding put to rest a longstanding debate in cell biology and spurred the researchers to find a better way to kill cancers.
The gate to mitotic exit can be opened by a large enzyme called the anaphase-promoting complex (APC), which marks important cell cycle molecules for degradation. Huang handcuffed the APC by knocking down one of its adapter proteins, Cdc20, thereby keeping cancer cells locked in mitosis. Working in several different tumor cell lines, she also halted mitotic exit by inhibiting other key orchestrators of the process. She then compared these manipulations to a standard spindle-disrupting treatment. Both strategies were equally effective at killing tumor cells that responded to standard treatment. But in more troublesome tumor cells, such as those resistant to cell death or prone to slipping out of division mode, targeting Cdc20 was far more effective.
Mitchison cautions against making assumptions about this strategy’s effectiveness in actual tumors. He also notes that just like current chemotherapies, this approach would have undesirable effects on noncancerous proliferating cells. But, he says, from talking to oncologists, it appears that eradicating tumors is still the biggest challenge. And his team’s hope is that more cancer cells would die with treatments that block mitotic exit.
“We felt that if you make such a bold title of a paper, you ought to do something about it,” Mitchison said of their study, Evidence that Mitotic Exit is a Better Cancer Therapeutic Target than Spindle Assembly. So Huang and another member of the lab, microscopy specialist Zac Cooper, in conjunction with the ICCB-Longwood Screening Facility, have performed a small-molecule screen for bioactive compounds that might mimic the Cdc20 manipulation. The results are still pending further analysis.
“This is a beautiful example of how increasingly detailed knowledge of cellular pathways may translate into more effective targeted therapies for cancer,” said Daniel Haber, the Kurt J. Isselbacher/Peter D. Schwartz professor of medicine at HMS and Massachusetts General Hospital and director of the MGH Cancer Center. “In this case, there are superficial similarities in the effects of many drugs that interfere with cell cycle checkpoints, but the precise insight into the various components that regulate mitotic exit may make it possible to bypass a common drug resistance mechanism. The proof that this works will, of course, depend on clinical trials, but this is a very exciting and novel approach to targeting a well-established vulnerability of cancer cells.”
Students may contact timothy_mitchison@hms.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflict of interest.
Funding Sources: The National Institutes of Health; the authors are solely responsible for the content of this work.
