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Molecules 2018, 23(12), 3175; https://doi.org/10.3390/molecules23123175

S5, a Withanolide Isolated from Physalis Pubescens L., Induces G2/M Cell Cycle Arrest via the EGFR/P38 Pathway in Human Melanoma A375 Cells

1,2,†
,
2,†
,
2
,
2,3
,
1,2
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1,2
,
2,3,* and 1,*
1
Department of Biochemistry, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
2
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
3
Department of Pharmaceutical Chemistry, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 23 October 2018 / Revised: 25 November 2018 / Accepted: 29 November 2018 / Published: 1 December 2018
(This article belongs to the Special Issue Herbal Medicines–Unraveling Their Molecular Mechanism)
PDF [7057 KB, uploaded 1 December 2018]

Abstract

S5 is a withanolide natural product isolated from Physalis pubescens L. Our previous experimental studies found that it has significant antitumor activity on renal cell carcinoma. In the present study, the anti-melanoma effect of S5 and the related molecular mechanism was first investigated. It was found that S5 induced an obvious growth inhibitory effect on human melanoma A375 cells with low toxicity to human peripheral blood cells. Furthermore, the results demonstrated that the cell death mode of S5 on A375 cells is not due to inducing apoptosis and autophagy. However, there was a significant time-dependent increase in G2/M phase after treatment of A375 with S5. Meanwhile, S5 could also decrease the protein expression of Cdc25c, Cdc2, and CyclinB1, and increased the expression of p-P53 and P21, suggesting that S5 inhibited A375 cell death through G2/M phase arrest. Moreover, the signal pathway factors P38, extracellular regulated protein kinases (ERK), and epidermal growth factor receptor (EGFR) were observed taking part in the S5-induced A375 cells growth inhibitory effect. In addition, suppressing P38 and EGFR reversed the cell proliferation inhibitory effect and G2/M cell cycle arrest induced by S5 and inhibition of EGFR enhanced the downregulation of the expression of P38 and p-P38, indicating that S5 induced A375 G2/M arrest through the EGFR/P38 pathway. Briefly, this study explained for the first time the mechanism of S5-induced A375 cell growth inhibition in order to provide the basis for its clinical application in melanoma.
Keywords: S5; G2/M arrest; EGFR; P38; melanoma S5; G2/M arrest; EGFR; P38; melanoma
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Fan, Y.; Mao, Y.; Cao, S.; Xia, G.; Zhang, Q.; Zhang, H.; Qiu, F.; Kang, N. S5, a Withanolide Isolated from Physalis Pubescens L., Induces G2/M Cell Cycle Arrest via the EGFR/P38 Pathway in Human Melanoma A375 Cells. Molecules 2018, 23, 3175.

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