Title:
Chromosome passengers control hidden explosives on board a mitotic flight

Masaaki Tatsuka¹ , Tomoharu Miki¹ , Mayumi Okamoto¹ , Satomi Koga¹ , Kenta Watanabe¹ , Yuki Nakahara¹ , Sanae Koya¹ , Mikiko Fujii¹ , and Takahide Ota²

¹ Laboratory of Radiation Genome Systems Biology, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shoubara 727-0023, HIROSHIMA, JAPAN
² Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada 920-0293, ISHIKAWA , JAPAN

Abstract:
　 Mitosis is a process of eukaryotic cell division resulting in the production of two daughter cells from a single parent cell. This process is nuclear division plus cytokinesis. The chromosome passengers including Aurora-B, inner centromere protein (INCENP), Survivin, and Borealin, travel with chromosomes during mitosis and control this process. If one of them is absent from the passenger complex, the mitotic events such as chromosome condensation, chromosome alignment, spindle checkpoint regulation, and cytokinesis are impaired. The cells defective in chromosome passenger function, however, complete the first mitosis due to their spindle checkpoint defects. The resulting daughter cells are destined by p53-dependent checkpoint regulation or cause multinuclearity.
　 In cancer cells, a member/members of the chromosome passengers is/are overexpressed. The overexpression affects chromosome segregation and cytokinesis. In addition, the overexpression of chromosome passengers promotes tumor growth both in vitro and in vivo . Interestingly, it also promotes cancer metastasis. To clarify why the overexpressed chromosome passengers promote cancer metastasis, we examined which metastasis-related biological processes were linked to the chromosome passenger function. Transfection experiments or inhibitor treatment experiments indicated that the cell motility, the cell-to-matrix attachment, and the matrix metalloproteinase activity were not related to the chromosome passengers. On the other hand, the reduced susceptibility to anoikis was implicated in the chromosome passenger function. Anoikis is a form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix. This biological event contributes to remove metastasis-competent living cells from vessel.
　 During mitosis, cytoskeletal architecture and nuclear organization are disassembled and remodeled. Accompanied with this process , the cell-to-matrix attachment system is also altered. The chromosome passenger regulates cell survival during mitosis, in addition to chromosome segregation and cytokinesis. Once spindle checkpoint regulation is activated, the chromosome passengers arrest the cells in metaphase prior to anaphase and prevent anoikis. Cancer cells would utilize anoikis resistance, a part of spindle checkpoint mechanisms, to establish metastasis. In this line, recent clinical trials of Aurora-B inhibitors to patients having poor prognostic features are showing that the chromosome passengers are promising molecular targets for cancer. The inhibitors might cause anoikis as well as mitotic failure in metastatic cancer cells.
　 Additionally, we will present our recent findings regarding other molecules associated with the chromosome passenger members. These passenger-related molecules including tRNA methyltransferase and poly (ADP-ribose) polymerase provide new insight into possible mechanisms to regulate cell fate through mitosis.