Int J Med Sci 2020; 17(3):403-413. doi:10.7150/ijms.41177

Research Paper

Hinokitiol reduces tumor metastasis by inhibiting heparanase via extracellular signal-regulated kinase and protein kinase B pathway

Yueh-Jung Wu1, Wei-Jie Hsu2, Li-Hsien Wu2, Huei-Pu Liou1, Christian Ronquillo Pangilinan2, Yu-Chang Tyan3, Che-Hsin Lee2,4,5,6✉

1. Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
2. Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
3. Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
4. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
5. Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
6. Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan

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Citation:
Wu YJ, Hsu WJ, Wu LH, Liou HP, Pangilinan CR, Tyan YC, Lee CH. Hinokitiol reduces tumor metastasis by inhibiting heparanase via extracellular signal-regulated kinase and protein kinase B pathway. Int J Med Sci 2020; 17(3):403-413. doi:10.7150/ijms.41177. Available from http://www.medsci.org/v17p0403.htm

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Abstract

Heparanase cleaves the extracellular matrix by degrading heparan sulfate that ultimately leads to cell invasion and metastasis; a condition that causes high mortality among cancer patients. Many of the anticancer drugs available today are natural products of plant origin, such as hinokitiol. In the previous report, it was revealed that hinokitiol plays an essential role in anti-inflammatory and anti-oxidation processes and promote apoptosis or autophagy resulting to the inhibition of tumor growth and differentiation. Therefore, this study explored the effects of hinokitiol on the cancer-promoting pathway in mouse melanoma (B16F10) and breast (4T1) cancer cells, with emphasis on heparanase expression. We detected whether hinokitiol can elicit anti-metastatic effects on cancer cells via wound healing and Transwell assays. Besides, mice experiment was conducted to observe the impact of hinokitiol in vivo. Our results show that hinokitiol can inhibit the expression of heparanase by reducing the phosphorylation of protein kinase B (Akt) and extracellular regulated protein kinase (ERK). Furthermore, in vitro cell migration assay showed that heparanase downregulation by hinokitiol led to a decrease in metastatic activity which is consistent with the findings in the in vivo experiment.

Keywords: heparanase, tumor metastasis, hinokitiol, protein kinase B, extracellular regulated protein kinase