Selective Killing Of Malignant Cancer Cells By Suppression Of Geminin Activity

摘要

Eukaryotic cells normally restrict genome duplication to once per cell division. In metazoa, re-replication of DNA during a single S-phase appears to be prevented solely by suppressing CDT1 activity, a protein required for loading the replicative MCM DNA helicase. However, siRNA suppression of geminin (a specific inhibitor of CDT1) arrested proliferation only of cells derived from malignant cancers by inducing DNA re-replication and DNA damage that spontaneously triggered apoptosis. None of these effects were detected either in cells derived from normal human tissues, or in cells immortalized by a viral oncogene. To induce these effects in non-cancer cells required suppression of both geminin and cyclin A, another cell cycle regulator. Therefore, initiating DNA replication in some cancer cells is limited solely by regulating the level of CDT1 activity with geminin, whereas non-cancer cells contain additional safeguards that prevent DNA re-replication. These results demonstrate that inhibition of geminin activity could be used to selectively kill cancer cells without harming other cells.