Some cancer drugs work by damaging tumor DNA so severely that cancer cells commit suicide. A City of Hope investigator recently showed how that self-destruct program gets switched on, suggesting strategies that might make cells more vulnerable to chemotherapy.
David Ann, Ph.D., professor in the Department of Clinical & Molecular Pharmacology, showed that when a cellular protein called ATM senses that DNA strands are badly broken, it instructs a cell to “self-destruct” by inactivating a protein that normally holds these cell-death signals in check.
These self-destruct signals are the body’s way of eliminating cells that are so damaged they cannot function healthfully.
Ann published the results in the Oct. 17 issue of the Journal of Biological Chemistry.
Several agents can activate ATM and stimulate cancer cell death. These include radiation and drugs like doxorubicin, which fights breast cancer by breaking strands of DNA in cancer cells.
Ann and collaborators showed that ATM begins its work following massive DNA damage. ATM switches off repressive signaling from a protein called KAP1, which normally makes sure that healthy cells do not selfdestruct. ATM does this in two steps. First, it removes a small protein called SUMO from KAP1. Then, for good measure, it marks KAP1 with another chemical tag.
But if SUMO can remain stuck to KAP1, that may keep cells from over-reacting to mild, repairable DNA damage, explained Ann. “We have demonstrated that addition of SUMO to KAP1 is a kind of a safety that makes sure that cells don’t respond to DNA damage with the kind of massive activation that would induce cell death,” he said.
Investigators demonstrated this through experiments with human breast cancer cells in a dish. They placed the KAP1 protein — with SUMO irreversibly stuck to it — into the cancer cells, and then treated the cells with doxorubicin.
Normally, the doxorubicin would kill the cells. But with KAP1 permanently locked in a safety position, the cells could not kill themselves.
“Our study suggests that KAP1 could be a useful marker to examine whether tumor cells will be responsive to radiation or DNA-damage reagents,” said Ann. “The less KAP1 they have, the better tumor cells should respond to radiation or chemotherapy.”
The study also suggests how tumor cells may resist doxorubicin therapy. It indicates that tumor cells actually resist the chemotherapy by throwing the KAP1 switch into reverse — that is, by sticking SUMO back onto inactivated KAP1.
Ann is collaborating with Yun Yen, M.D., Ph.D., director of the Department of Clinical & Molecular Pharmacology, to identify small molecules that might block this type of KAP1 re-activation.
Yen, a co-author of the study, describes his and Ann’s partnership this way: “I look for drugs, and he looks at mechanisms. We must understand the mechanism of drug resistance in cancer; when we do, we will be able to screen patients to help them make a decision about whether a particular type of treatment would be useful.”
Ann thinks that drugs that block KAP1 activation could be used as neoadjuvant therapy. Neoadjuvants are treatments given before radiation or chemotherapy to make cells more receptive to chemotherapy. In this case, giving patients a drug that eliminates or inactivates KAP1 in tumor cells before doxorubicin treatment could make cancer cells easier to eradicate.
Also contributing to the study were co-first author Xu Li, a University of Southern California (USC) graduate student, Yung-Kang Lee, Ph.D., a former graduate student in Ann’s lab at USC, Jen-Chong Jeng and Hsiu-Ming Shih, Ph.D., of the Institute of Biomedical Sciences in Taipei, Taiwan, and David Schultz, Ph.D., of the Wistar Institute in Philadelphia.
The National Institutes of Health and the Taiwan National Health Research Institute funded the study.
