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

Yuqi Fan, Yiwei Mao, Shijie Cao, Guiyang Xia, Qiang Zhang, Hongyang Zhang, Feng Qiu, Ning Kang

Journal: Molecules (Basel, Switzerland) 2019;23(12):3175

PMID: 30513793

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.

Address: Department of Biochemistry, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Department of Pharmaceutical Chemistry, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Department of Biochemistry, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Department of Biochemistry, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Department of Pharmaceutical Chemistry, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].; Department of Biochemistry, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China. [email protected].

DOI: 10.3390/molecules23123175

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MeSH Terms: Antineoplastic Agents, Phytogenic, Cell Line, Tumor, Cell Proliferation, ErbB Receptors, G2 Phase Cell Cycle Checkpoints, Humans, Molecular Structure, Physalis, Signal Transduction, Withanolides, p38 Mitogen-Activated Protein Kinases