Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells — Oak Academic Publishing
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Geldanamycin Combination with Colcemid Induces Mitotic Arrest through Stabilization of bubR1 Mitotic Kinase in Human Tumor Cells
CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
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CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
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CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
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CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
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CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
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CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
1 CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
2 CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
3 CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
4 CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
5 CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
6 CSIR—Centre for Cellular and Molecular Biology, Hyderabad, India
Mitosis-targeted anti-cancer therapies gained much attention in recent years. However, lack of tumor selectivity poses limitations to the current anti-mitotic drugs to be used as broad-spectrum anti-cancer agents. In this study, we show that combination treatment of colcemid, an inhibitor of microtubule polymerization with geldanamycin, an inhibitor of cancer chaperone, Hsp90 irreversibly targets mitosis through mitotic kinase bubR1 stabilization. When the individual and combination drugs treatments were tested against tumor cells (IMR-32 and HeLa) and non-tumor cells (SRA01), the combination treatment showed significant increase in cytotoxicity only in tumor cells followed by G2/M cell cycle block. The IMR-32 cells showed enhanced cytotoxicity in response to combination treatments, compared to HeLa cells. Further studies revealed that the G2/M arrest in IMR-32 correlates with both increased bubR1 nuclear localization and metaphase arrest. The siRNA knockdown of bubR1 has decreased tumor cell response to geldanamycin suggesting Hsp90-dependent regulation of bubR1. The combination treatment also showed inactivation of non-canonical β -catenin signaling suggesting inhibition of cancer growth. In addition, the combination treatment has significantly affected the distribution and functions of bubR1 downstream mitotic kinases such as aurks and plk1 indicating the combinatorial attack of combination treatment. In conclusion, we demonstrate that colcemid and GA combination treatment compromises the division potential of tumor cells interfering with the mitosis through bubR1 kinase.
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