Requirement of a functional spindle checkpoint for arsenic-induced mitotic death

2062

The spindle checkpoint is a key cell cycle control mechanism that ensures an accurate segregation of chromosomes during mitosis. Many anti-tumor drugs, including spindle assembly inhibitors and DNA damaging agents, can activate the spindle checkpoint. Accumulated evidences have demonstrated that a competent spindle checkpoint is required for anti-mitotic drugs to induce apoptosis. However, a weakened spindle checkpoint is frequently seen in cancer cells and might thereby hamper the therapeutic effect of anti-tumor drugs. Arsenic trioxide (ATO) has recently been proved effective in the treatment of refractory or relapsed acute promyelocytic leukemia and expansion of its therapeutic value to solid tumors is under extensive investigation. We have previously demonstrated that mitosis-mediated apoptosis was significantly induced by arsenite in a spindle checkpoint-dependent manner in a cervical cancer-derived cell line. In order to understand the potential influence of the spindle checkpoint in response to ATO, we examined the correlation between spindle checkpoint impairment and susceptibility to ATO-induced apoptosis in several cancer cell lines. The spindle checkpoint status of each cancer cell line was assessed by the induction of mitotic arrest after taxol treatment. Our results showed a significant difference in the susceptibility to apoptosis induced by ATO between spindle checkpoint-impaired and -proficient cell lines. In the spindle checkpoint-proficient cell lines, HeLa S-3 and CGL-4, when G1-synchronized cells were treated with ATO the cells were arrested at mitotic stage and followed by apoptosis. Conversely, in the spindle checkpoint-impaired cell lines, T24, C33-A, and H1299, the same treatment allowed all cells to progress through mitosis, cell division, and enter into the subsequent replication cycle. However, no such correlation was noticed after treating cells with campothecin, a topoisomerase I inhibitor. The marked association between ATO-induced mitotic arrest and apoptosis indicated that the integrity of spindle checkpoint might affect the susceptibility of cancer cells to ATO-induced apoptosis. Our finding indicated that the spindle checkpoint was involved in arsenite induction of apoptosis in cancer cells and has implications for effective use of ATO in cancer therapy.