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

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.

SUBMITTER: Fan Y

PROVIDER: S-EPMC6321527 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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

Fan Yuqi Y Mao Yiwei Y Cao Shijie S Xia Guiyang G Zhang Qiang Q Zhang Hongyang H Qiu Feng F Kang Ning N

Molecules (Basel, Switzerland) 20181201 12

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 ...[more]

PMID: 30513793

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Project description:Skin cancer is one of the most common cancers worldwide. Melanoma accounts for ~5% of skin cancers but causes the large majority of skin cancer?related deaths. Recent discoveries have shown that the mitogen?activated protein kinase (MAPK) signaling pathway is critical for melanoma development and progression. Many oncogenic pathways that cause melanoma tumorigenesis have been identified, most of which are due to RAF/MEK/ERK (MAPK) pathway activation. However, the precise role of p38 remains unclear. Using specific short hairpin (sh) RNA to silence p38? and p38?, the present findings demonstrated that p38? was a crucial factor in regulating cell migration in the A375 melanoma cell line. Silencing p38? downregulated the expression of epithelial?mesenchymal transition markers, such as matrix metallopeptidase (MMP) 2, MMP9, twist family bHLH transcription factor 1, snail family transcriptional repressor 1 and vimentin, while mesenchymal?epithelial transition markers, such as E?cadherin, were upregulated. Of note, the results also demonstrated that p38? silencing impaired vascular endothelial growth factor expression, which regulates tumor angiogenesis. Furthermore, p38? knockdown inhibited cell proliferation in melanoma cells. In addition, silencing p38? induced senescence?like features, but not cell cycle arrest. Expression of the senescence markers p16, p21, p53 and ??galactosidase was upregulated, and an increase in the number of senescence?associated ??galactosidase?positive cells was observed in a p38? knockdown stable clone. However, no significant difference was found between control and p38? stable knockdown cells. Taken together, the present results suggested that p38? knockdown impaired migration and proliferation, and increased senescence, in A375 melanoma cells. However, p38? may not be involved in melanoma tumorigenesis. Therefore, targeting p38? may be a valuable approach towards inhibiting tumor growth and metastasis in patients with melanoma.

Dataset Information

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

Publications

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

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