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Molecules 2018, 23(9), 2121; https://doi.org/10.3390/molecules23092121

JNK Inactivation Induces Polyploidy and Drug-Resistance in Coronarin D-Treated Osteosarcoma Cells

1,†
,
2,†
,
1,2
,
1,2,3,4,* and 1,*
1
Department of Orthopedic Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan
2
Orthopedics & Sports Medicine Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan
3
Institute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., South Dist, Taichung 40227, Taiwan
4
School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
These authors have contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 27 July 2018 / Revised: 19 August 2018 / Accepted: 21 August 2018 / Published: 23 August 2018
(This article belongs to the Special Issue Antitumoral Properties of Natural Products)
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Abstract

Inhibition of proliferating cells is a critical strategy for cancer therapy. In this study, we demonstrated that coronarin D, a natural component extracted from the rhizomes of Hedychium coronarium, significantly suppressed the proliferation of osteosarcoma cells. The treatment with coronarin D resulted in the activation of caspase-3 and apoptosis. This treatment induced the accumulation of cyclin B1 and DNA condensation indicating the treated osteosarcoma cells were arrested in mitotic phase. Furthermore, the treatment with coronarin D increased the levels of phosphorylated c-Jun NH2-terminal kinase (JNK) in human osteosarcoma cells. Pretreatment with JNK inhibitor blocked the accumulation of cyclin B1 and DNA condensation, resulting the accumulation of tetraploid cells in coronarin D-treated osteosarcoma HOS cells, indicating JNK inactivation blocked the mitotic entry and arrested cells in the 4 N state. After adaptation, the arrested tetraploid cells continued to duplicate their DNA resulting in polyploidy. Interestingly, when the arrested mitotic cells induced by coronarin D were treated with JNK inhibitor, the accumulated cyclin B1 and DNA condensation were immediately eliminated. These arrested 4 N cells loss the ability to undergo cytokinesis, and ultimately continued to duplicate DNA upon prolonged arrest resulting in the production of polyploid populations. JNK inactivation, either by the pretreatment with JNK inhibitor or the treatment with JNK inhibitor in coronarin D-induced mitotic cells, both caused resistance to coronarin D-induced cell death. Taken together, our findings indicate that coronarin D induces the apoptosis and mitosis arrest in human osteosarcoma cells. JNK has a crucial role in coronarin D-induced mitosis arrest and apoptosis. We hypothesize that functional evaluation of JNK may produce more specific and effective therapies in coronarin D-related trail for treatment of human osteosarcoma. View Full-Text
Keywords: coronarin D; JNK; osteosarcoma coronarin D; JNK; osteosarcoma
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Hsu, C.-T.; Huang, Y.-F.; Hsieh, C.-P.; Wu, C.-C.; Shen, T.-S. JNK Inactivation Induces Polyploidy and Drug-Resistance in Coronarin D-Treated Osteosarcoma Cells. Molecules 2018, 23, 2121.

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