Inhibition of AKT enhances mitotic cell apoptosis induced by arsenic trioxide.
Accumulated evidence has revealed a tight link between arsenic trioxide (ATO)-induced apoptosis and mitotic arrest in cancer cells. AKT, a serine/threonine kinase frequently over-activated in diverse tumors, plays critical roles in stimulating cell cycle progression, abrogating cell cycle checkpoints, suppressing apoptosis, and regulating mitotic spindle assembly. Inhibition of AKT may therefore enhance ATO cytotoxicity and thus its clinical utility. We show that AKT was activated by ATO in HeLa-S3 cells. Inhibition of AKT by inhibitors of the phosphatidyl inositol 3-kinase/AKT pathway significantly enhanced cell sensitivity to ATO by elevating mitotic cell apoptosis. Ectopic expression of the constitutively active AKT1 had no effect on ATO-induced spindle abnormalities but reduced kinetochore localization of BUBR1 and MAD2 and accelerated mitosis exit, prevented mitotic cell apoptosis, and enhanced the formation of micro- or multi-nuclei in ATO-treated cells. These results indicate that AKT1 activation may prevent apoptosis of ATO-arrested mitotic cells by attenuating the function of the spindle checkpoint and therefore allowing the formation of micro- or multi-nuclei in surviving daughter cells. In addition, AKT1 activation upregulated the expression of aurora kinase B (AURKB) and survivin, and depletion of AURKB or survivin reversed the resistance of AKT1-activated cells to ATO-induced apoptosis. Thus, AKT1 activation suppresses ATO-induced mitotic cell apoptosis, despite the presence of numerous spindle abnormalities, probably by upregulating AURKB and survivin and attenuating spindle checkpoint function. Inhibition of AKT therefore effectively sensitizes cancer cells to ATO by enhancing mitotic cell apoptosis.
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC. lhyih@gate.sinica.edu.tw
Ling-Huei
LH
Yih
Nai-Chi
NC
Hsu
Yi-Chen
YC
Wu
Wen-Yen
WY
Yen
Hsiao-Hui
HH
Kuo
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D010087:Oxides / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D001152:Arsenicals; D006131:Growth Inhibitors; D010087:Oxides; D051057:Proto-Oncogene Proteins c-akt; D000077237:Arsenic Trioxide