The signaling mechanisms linking mitotic arrest with apoptosis.

摘要

In an adult organism, cell division and apoptosis are closely regulated and balanced. When this balance mechanism fails, pathological conditions may develop. For example, cancer will be formed when there is too less apoptosis. Thus the treatment of cancer is usually dependent on the activation of apoptosis. An important class of cancer chemotherapeutic agents is the microtubule interfering agents (MIAs), which can either stabilize or depolymerize microtubules. Such agents, including Taxol, Vincristine and Vinblastine, can lead to mitotic arrest and then apoptosis. It has been demonstrated that the mechanism of MIAs-induced cytotoxicity in cancer cells is mainly through apoptosis. However, the mechanisms responsible for directing mitotic arrest to apoptosis are still unknown. This study is to investigate the signaling mechanisms linking mitotic arrest with apoptosis. Using living cell image combined with molecular genetic tools, we found that CDK1 plays important roles in linking mitotic arrest with apoptosis. CDK1 can phosphorylate some of Bcl-2/Bax family proteins including Bcl-2, Mcl-1 and Bad and modify their functions. The anti-apoptotic function of Bcl-2 was enhanced upon its phosphorylation, while phosphorylated Mcl-1 inactivated its anti-apoptotic function and phosphorylated Bad enhanced its pro-apoptotic function. The destination of cells under MIAs treatment depends on a balance between the altered pro- and anti-apoptotic functions of the phosphorylated proteins. Based on the approach of mitotic arrest-induced apoptosis, we tried to search new anti-cancer drugs from Traditional Chinese Medicine (TCM). We found that DT2A, an important component of a TCM, can arrest HeLa cells in mitosis and lead cells to undergo apoptosis. And DT2A has a strong potency to kill dividing cells than interphase cells. It has no cytotoxic effect on non-transformed cells. These characteristics of DT2A make it a good candidate for anti-cancer drugs.