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Anti-tumor Drug THZ1 Suppresses TGF?2-mediated EMT in Lens Epithelial Cells via Notch and TGF?/Smad Signaling Pathway.

ABSTRACT: Selective covalent CDK7 inhibitor THZ1 is a promising potential anti-tumor drug in many kinds of cancers. Epithelial-mesenchymal Transition (EMT) is highly related to cancer initiation, development, invasion and metastasis and other pathogenesis processes. We treated cancer cell line Hela229 and three retinoblastoma cell lines so-RB50, WERI-Rb-1, Y79 with gradient concentration of THZ1, and found that THZ1 could inhibit cell viability and EMT, suggesting that THZ1 may be a promising drug for human cervical cancer and retinoblastoma treatment. Our results verified the role of THZ1 in EMT for the first time, however, the mechanism needs further study. Here we report that THZ1 suppresses the TGF?2 induced EMT in human SRA01/04 lens epithelial cells (LECs), rabbit primary lens epithelial cells, and whole rat lens culture semi-in vivo model. RNA-sequencing and KEGG analysis revealed that the THZ1 inhibits EMT by down-regulating phosphorylate Smad2 and Notch signaling pathway. On the other hand, we found that THZ1 could strongly inhibit LECs proliferation through G2/M phase arrest as well as attenuating of MAPK, PI3K/AKT signaling pathway. Our results uncovered the function and underlying mechanism of THZ1 in regulation of EMT, which provides a new perspective of the anti-tumor effect by THZ1 and may offer a novel treatment for PCO.

SUBMITTER: Ning J

PROVIDER: S-EPMC6636287 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Anti-tumor Drug THZ1 Suppresses TGFβ2-mediated EMT in Lens Epithelial Cells via Notch and TGFβ/Smad Signaling Pathway.

Ning Jie J Ma Xinqi X Long Chongde C Mao Yuxiang Y Kuang Xielan X Huang Zixin Z Fan Yuting Y Zhang Han H Xia Qing Q Wang Renchun R Liang Yu Y Lin Shuibin S Zhang Qingjiong Q Shen Huangxuan H

Journal of Cancer 20190609 16

Selective covalent CDK7 inhibitor THZ1 is a promising potential anti-tumor drug in many kinds of cancers. Epithelial-mesenchymal Transition (EMT) is highly related to cancer initiation, development, invasion and metastasis and other pathogenesis processes. We treated cancer cell line Hela229 and three retinoblastoma cell lines so-RB50, WERI-Rb-1, Y79 with gradient concentration of THZ1, and found that THZ1 could inhibit cell viability and EMT, suggesting that THZ1 may be a promising drug for hum ...[more]

PMID: 31333795

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Project description:BACKGROUND:The signaling pathway of epithelial to mesenchymal transition (EMT) is regulated by c-Src kinase in many cells. The purpose of this study was to investigate the effects of c-Src kinase on EMT of human lens epithelial cells in vivo stimulated by different factors. METHODS:Human lens epithelial cells, HLE-B3, were exposed to either an inflammatory factor, specifically IL-1?, IL-6, TNF-? or IL-1?, at 10?ng/mL or high glucose (35.5?mM) for 30 mins. Activity of c-Src kinase was evaluated by the expression of p-Src418 with western blot assay. To investigate the effects of activation of c-Src on EMT, HLE-B3 cells were transfected with pCDNA3.1-SrcY530F to upregulate activity of c-Src kinase, and pSlience4.1-ShSrc to knock it down. The expressions of c-Src kinase and molecular markers of EMT such as E-cadherin, ZO-1, ?-SMA, and Vimentin were examined at 48?h by RT-PCR and western blot. At 48?h and 72?h of transfection, cell proliferation was detected by MTT, and cell mobility and migration were determined by scratch and transwell assays. RESULTS:Activity of c-Src kinase, which causes the expression of p-Src418, was upregulated by different inflammatory factors and high glucose in HLE-B3 cells. When HLE-B3 cells were transfected with pCDNA3.1-SrcY530F, the expression of c-Src kinase was upregulated on both mRNA and protein levels, and activity of c-Src kinase, expression of p-Src418 increased. The expressions of both E-cadherin and ZO-1 were suppressed, while the expressions of vimentin and ?-SMA were elevated on both mRNA and protein levels at the same time. Cell proliferation, mobility and migration increased along with activation of c-Src kinase. Conversely, when HLE-B3 cells were transfected with pSlience4.1-ShSrc, both c-Src kinase and p-Src418 expressions were knocked down. The expressions of E-cadherin and ZO-1 increased, but the expressions of Vimentin and ?-SMA decreased; meanwhile, cell proliferation, mobility and migration reduced. CONCLUSIONS:The c-Src kinase in lens epithelial cells is easily activated by external stimuli, resulting in the induction of cell proliferation, mobility, migration and EMT.

Dataset Information

Anti-tumor Drug THZ1 Suppresses TGF?2-mediated EMT in Lens Epithelial Cells via Notch and TGF?/Smad Signaling Pathway.

Publications

Anti-tumor Drug THZ1 Suppresses TGFβ2-mediated EMT in Lens Epithelial Cells via Notch and TGFβ/Smad Signaling Pathway.

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