Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells

Mo, Lijun; Xu, Lili; Jia, Min; Su, Bijia; Hu, Yaolong; Hu, Zhiming; Li, Hongwei; Zhao, Chenye; Zhao, Zhenlin; Li, Jinlong

doi:10.7150/jca.63429

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J Cancer 2021; 12(22):6814-6824. doi:10.7150/jca.63429 This issue Cite

Research Paper

Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells

Lijun Mo^1,2, Lili Xu^1,2, Min Jia^2,3, Bijia Su^1,2, Yaolong Hu¹, Zhiming Hu¹, Hongwei Li¹, Chenye Zhao², Zhenlin Zhao^2✉, Jinlong Li^1,2✉

1. Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
2. Shenzhen Ruipuxun Academy for Stem Cell & Regenerative Medicine, 14 Jinhui Road, Shenzhen 518118, People's Republic of China.
3. Department of Clinical Laboratory, Dermatology Hospital, Southern Medical University, Guangzhou, China.

Citation:

Mo L, Xu L, Jia M, Su B, Hu Y, Hu Z, Li H, Zhao C, Zhao Z, Li J. Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells. J Cancer 2021; 12(22):6814-6824. doi:10.7150/jca.63429. https://www.jcancer.org/v12p6814.htm

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Abstract

Shikonin (SK) is the major bioactive component extracted from the roots of Lithospermum erythrorhizon with anticancer activity. SK could inhibit the epithelial-to-mesenchymal transition (EMT) of cancer cells. However, the underlying mechanism is elusive. In the present study, the inhibitory activities of SK on proliferation, invasion and migration were examined in bladder cancer (BC) cells. SK potently decreased the viabilities of BC cells but showed less cytotoxicity to normal bladder epithelial cells. Moreover, SK reversed the EMT, suppressed the migration and invasion of BC cells. Intriguingly, NHE1, the major proton efflux pump, was dramatically down-regulated by SK. The EMT-inhibitory effect of SK was mediated by NHE1 down-regulation, as NHE1-overexpress alleviated while Cariporide (NHE1 inhibitor) enhanced this effect. Further, enforced alkalinization of intracellular pH (pHi) reversed the EMT-inhibitory effect of SK, indicating a key role of acidic pHi in this process. Finally, elevated NHE1 expression was observed in human bladder cancer tissues. Collectively, this research reveals a supportive effect of NHE1 and alkaline pHi on EMT. SK can suppress EMT through inhibiting NHE1 and hence inducing an acidic pHi.

Keywords: shikonin, EMT, intracellular pH, NHE1, glycolysis

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APA

Mo, L., Xu, L., Jia, M., Su, B., Hu, Y., Hu, Z., Li, H., Zhao, C., Zhao, Z., Li, J. (2021). Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells. Journal of Cancer, 12(22), 6814-6824. https://doi.org/10.7150/jca.63429.

ACS

Mo, L.; Xu, L.; Jia, M.; Su, B.; Hu, Y.; Hu, Z.; Li, H.; Zhao, C.; Zhao, Z.; Li, J. Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells. J. Cancer 2021, 12 (22), 6814-6824. DOI: 10.7150/jca.63429.

NLM

CSE

Mo L, Xu L, Jia M, Su B, Hu Y, Hu Z, Li H, Zhao C, Zhao Z, Li J. 2021. Shikonin suppresses the epithelial-to-mesenchymal transition by downregulating NHE1 in bladder cancer cells. J Cancer. 12(22):6814-6824.

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