Aurora B kinase as a novel molecular target for inhibition the growth of osteosarcoma

Zhenjiang Zhao; Guoguo Jin; Ke Yao; Kangdong Liu; Fangfang Liu; Hanyong Chen; Keke Wang; Dhilli Rao Gorja; Srinivasa Reddy Kanamata Reddy; Ann M. Bode; Zhiping Guo; Zigang Dong

doi:10.1002/mc.22993

Aurora B kinase as a novel molecular target for inhibition the growth of osteosarcoma

Zhenjiang Zhao, Guoguo Jin, Ke Yao, Kangdong Liu, Fangfang Liu, Hanyong Chen, Keke Wang, Dhilli Rao Gorja, Srinivasa Reddy Kanamata Reddy, Ann M. Bode, Zhiping Guo, Zigang Dong

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

Osteosarcoma is the primary human malignant tumor affecting bone. This cancer most frequently arises in children and adolescents, with a second peak in those over the age of 50. Currently, surgery followed by radiotherapy and chemotherapy are the main treatments, but long-term positive effects are very poor. Aurora B kinase is a serine/threonine kinase that is a key regulator of cell cycle and mitosis. Tissue array analysis revealed that Aurora B kinase is overexpressed in osteosarcoma compared with normal bone tissue. We developed a compound, HOI-07 (i.e., (E)-3-((E)-4-(benzo[d] [1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one), as a specific Aurora B kinase inhibitor and examined its effectiveness against osteosarcoma cell growth in this study. This compound inhibited Aurora B kinase activity in osteosarcoma and induced apoptosis, caused G2-M phase arrest, and attenuated osteosarcoma anchorage-independent cell growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of osteosarcoma to HOI-07. Results of a xenograft mouse study indicated that HOI-07 treatment effectively suppressed the growth of 143B and KHOS xenografts, without affecting the body weight of mice. The expression of phosphorylated histone H3 (Ser10) was reduced in mice treated with HOI-07. Overall, we identified HOI-07 as a specific Aurora B kinase inhibitor for osteosarcoma treatment and this compound warrants further investigation.

Original language	English (US)
Pages (from-to)	1056-1067
Number of pages	12
Journal	Molecular Carcinogenesis
Volume	58
Issue number	6
DOIs	https://doi.org/10.1002/mc.22993
State	Published - Jun 2019

Bibliographical note

Funding Information:
National Natural Science Foundation of China, Grant/Award Number: 162300410337; National Institutes of Health, Grant/Award Numbers: CA187027, CA196639, CA166011; Mayo Clinic; Hormel Institute, University of Minnesota; Hormel Foundation and National Institutes of Health

Funding Information:
We thank Dr John R. Hawse, Dr Avudaiappan Maran, and Dr Thomas C. Spelsberg (Mayo Clinic) for the gifts of osteoblasts and osteosarcoma cells. We thank Todd Schuster for assisting with flow cytometry experiments, and Nicki Brickman for assistance in submitting our manuscript (The Hormel Institute, University of Minnesota). This study was funded by The Hormel Foundation and National Institutes of Health (grants CA166011, CA187027, and CA196639) and a Joint Funds of the National Natural Science Foundation of China (Grant no. 162300410337).

Publisher Copyright:
© 2019 Wiley Periodicals, Inc.

Keywords

Aurora kinases
HOI-07
mitosis
osteosarcoma
targeted therapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/mc.22993

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title = "Aurora B kinase as a novel molecular target for inhibition the growth of osteosarcoma",

abstract = "Osteosarcoma is the primary human malignant tumor affecting bone. This cancer most frequently arises in children and adolescents, with a second peak in those over the age of 50. Currently, surgery followed by radiotherapy and chemotherapy are the main treatments, but long-term positive effects are very poor. Aurora B kinase is a serine/threonine kinase that is a key regulator of cell cycle and mitosis. Tissue array analysis revealed that Aurora B kinase is overexpressed in osteosarcoma compared with normal bone tissue. We developed a compound, HOI-07 (i.e., (E)-3-((E)-4-(benzo[d] [1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one), as a specific Aurora B kinase inhibitor and examined its effectiveness against osteosarcoma cell growth in this study. This compound inhibited Aurora B kinase activity in osteosarcoma and induced apoptosis, caused G2-M phase arrest, and attenuated osteosarcoma anchorage-independent cell growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of osteosarcoma to HOI-07. Results of a xenograft mouse study indicated that HOI-07 treatment effectively suppressed the growth of 143B and KHOS xenografts, without affecting the body weight of mice. The expression of phosphorylated histone H3 (Ser10) was reduced in mice treated with HOI-07. Overall, we identified HOI-07 as a specific Aurora B kinase inhibitor for osteosarcoma treatment and this compound warrants further investigation.",

keywords = "Aurora kinases, HOI-07, mitosis, osteosarcoma, targeted therapy",

author = "Zhenjiang Zhao and Guoguo Jin and Ke Yao and Kangdong Liu and Fangfang Liu and Hanyong Chen and Keke Wang and Gorja, {Dhilli Rao} and {Kanamata Reddy}, {Srinivasa Reddy} and Bode, {Ann M.} and Zhiping Guo and Zigang Dong",

note = "Funding Information: National Natural Science Foundation of China, Grant/Award Number: 162300410337; National Institutes of Health, Grant/Award Numbers: CA187027, CA196639, CA166011; Mayo Clinic; Hormel Institute, University of Minnesota; Hormel Foundation and National Institutes of Health Funding Information: We thank Dr John R. Hawse, Dr Avudaiappan Maran, and Dr Thomas C. Spelsberg (Mayo Clinic) for the gifts of osteoblasts and osteosarcoma cells. We thank Todd Schuster for assisting with flow cytometry experiments, and Nicki Brickman for assistance in submitting our manuscript (The Hormel Institute, University of Minnesota). This study was funded by The Hormel Foundation and National Institutes of Health (grants CA166011, CA187027, and CA196639) and a Joint Funds of the National Natural Science Foundation of China (Grant no. 162300410337). Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",

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language = "English (US)",

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AU - Zhao, Zhenjiang

AU - Jin, Guoguo

AU - Yao, Ke

AU - Liu, Kangdong

AU - Liu, Fangfang

AU - Chen, Hanyong

AU - Wang, Keke

AU - Gorja, Dhilli Rao

AU - Kanamata Reddy, Srinivasa Reddy

AU - Bode, Ann M.

AU - Guo, Zhiping

AU - Dong, Zigang

N1 - Funding Information: National Natural Science Foundation of China, Grant/Award Number: 162300410337; National Institutes of Health, Grant/Award Numbers: CA187027, CA196639, CA166011; Mayo Clinic; Hormel Institute, University of Minnesota; Hormel Foundation and National Institutes of Health Funding Information: We thank Dr John R. Hawse, Dr Avudaiappan Maran, and Dr Thomas C. Spelsberg (Mayo Clinic) for the gifts of osteoblasts and osteosarcoma cells. We thank Todd Schuster for assisting with flow cytometry experiments, and Nicki Brickman for assistance in submitting our manuscript (The Hormel Institute, University of Minnesota). This study was funded by The Hormel Foundation and National Institutes of Health (grants CA166011, CA187027, and CA196639) and a Joint Funds of the National Natural Science Foundation of China (Grant no. 162300410337). Publisher Copyright: © 2019 Wiley Periodicals, Inc.

PY - 2019/6

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N2 - Osteosarcoma is the primary human malignant tumor affecting bone. This cancer most frequently arises in children and adolescents, with a second peak in those over the age of 50. Currently, surgery followed by radiotherapy and chemotherapy are the main treatments, but long-term positive effects are very poor. Aurora B kinase is a serine/threonine kinase that is a key regulator of cell cycle and mitosis. Tissue array analysis revealed that Aurora B kinase is overexpressed in osteosarcoma compared with normal bone tissue. We developed a compound, HOI-07 (i.e., (E)-3-((E)-4-(benzo[d] [1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one), as a specific Aurora B kinase inhibitor and examined its effectiveness against osteosarcoma cell growth in this study. This compound inhibited Aurora B kinase activity in osteosarcoma and induced apoptosis, caused G2-M phase arrest, and attenuated osteosarcoma anchorage-independent cell growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of osteosarcoma to HOI-07. Results of a xenograft mouse study indicated that HOI-07 treatment effectively suppressed the growth of 143B and KHOS xenografts, without affecting the body weight of mice. The expression of phosphorylated histone H3 (Ser10) was reduced in mice treated with HOI-07. Overall, we identified HOI-07 as a specific Aurora B kinase inhibitor for osteosarcoma treatment and this compound warrants further investigation.

AB - Osteosarcoma is the primary human malignant tumor affecting bone. This cancer most frequently arises in children and adolescents, with a second peak in those over the age of 50. Currently, surgery followed by radiotherapy and chemotherapy are the main treatments, but long-term positive effects are very poor. Aurora B kinase is a serine/threonine kinase that is a key regulator of cell cycle and mitosis. Tissue array analysis revealed that Aurora B kinase is overexpressed in osteosarcoma compared with normal bone tissue. We developed a compound, HOI-07 (i.e., (E)-3-((E)-4-(benzo[d] [1,3]dioxol-5-yl)-2-oxobut-3-en-1-ylidene)indolin-2-one), as a specific Aurora B kinase inhibitor and examined its effectiveness against osteosarcoma cell growth in this study. This compound inhibited Aurora B kinase activity in osteosarcoma and induced apoptosis, caused G2-M phase arrest, and attenuated osteosarcoma anchorage-independent cell growth. Moreover, knocking down the expression of Aurora B effectively reduced the sensitivity of osteosarcoma to HOI-07. Results of a xenograft mouse study indicated that HOI-07 treatment effectively suppressed the growth of 143B and KHOS xenografts, without affecting the body weight of mice. The expression of phosphorylated histone H3 (Ser10) was reduced in mice treated with HOI-07. Overall, we identified HOI-07 as a specific Aurora B kinase inhibitor for osteosarcoma treatment and this compound warrants further investigation.

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Aurora B kinase as a novel molecular target for inhibition the growth of osteosarcoma

Abstract

Bibliographical note

Keywords

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