Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways

Hsin-Lin Cheng; Chiao-Wen Lin; Jia-Sin Yang; Ming-Ju Hsieh; Shun-Fa Yang; Ko-Hsiu Lu

doi:10.18632/oncotarget.7138

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Research Papers:

Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways

Hsin-Lin Cheng _, Chiao-Wen Lin, Jia-Sin Yang, Ming-Ju Hsieh, Shun-Fa Yang and Ko-Hsiu Lu

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Oncotarget. 2016; 7:9742-9758. https://doi.org/10.18632/oncotarget.7138

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Abstract

Hsin-Lin Cheng1,2, Chiao-Wen Lin3,4, Jia-Sin Yang1,2, Ming-Ju Hsieh1,5, Shun-Fa Yang1,2, Ko-Hsiu Lu6,7

1Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan

2Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

3Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan

4Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

5Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan

6Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 40201, Taiwan

7School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan

Correspondence to:

Shun-Fa Yang, e-mail: [email protected]

Ko-Hsiu Lu, e-mail: [email protected]

Keywords: geranylgeranylation, metastasis, Rho A, U2OS, zoledronate

Received: September 30, 2015 Accepted: January 20, 2016 Published: February 02, 2016

ABSTRACT

Zoledronate is a standard treatment for preventing skeletal complications of osteoporosis and some types of cancer associated with bone metastases, but we little know whether the effect of zoledronate on metastasis of osteosarcoma. Here, we investigated the inhibitory effects of zoledronate on cell viability, motility, migration and invasion of 4 osteosarcoma cell lines (Saos2, MG-63, HOS and U2OS) by affecting cell morphology, epithelial-mesenchymal transition (EMT) and cytoskeletal organization as well as induction of E-cadherin and reduction of N-cadherin with activation of transcription factors Slug and Twist, especially in U2OS cells. Zoledronate decreased JNK and p38 phosphorylation and upper streams of focal adhesion kinase (FAK) and Src to suppress the motility, invasiveness and migration of U2OS cells. In addition to zoledronate-inhibited Rho A and Cdc42 membrane translocation and GTPγS activities, the anti-metastatic effects in U2OS cells including inhibition of adhesion were reversed by geranylgeraniol, but not farnesol. In conclusion, Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cell-matrix and cell-cell interactions, migration potential, the invasive activity, and the adhesive ability by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.

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Research Papers:

Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways

Abstract