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Novel Compound C150 Inhibits Pancreatic Cancer Cell Epithelial-to-Mesenchymal Transition and Tumor Growth in Mice.

ABSTRACT: Pancreatic cancer cell epithelial-to-mesenchymal transition (EMT) is an important contributor to cell invasion and tumor progression. Therefore, targeting EMT may be beneficial for pancreatic cancer treatment. The aim of the present study was to report on the inhibitory effect of the novel compound C150 on the EMT of pancreatic cancer cells. C150 inhibited cell proliferation in multiple pancreatic cancer cells with IC₅₀ values of 1-2.5 μM, while in an non-cancerous pancreatic epithelial cell line hTERT-HPNE the IC₅₀ value was >12.5 μM. C150 significantly inhibited pancreatic cancer cell migration and invasion, as demonstrated by 3-dimensional cell invasion, wound healing and Boyden chamber Transwell migration-invasion assays. Moreover, C150 treatment decreased MMP-2 gene expression in PANC-1 cells and reduced MMP-2 activity in gelatin zymography assay. In an orthotopic mouse model of pancreatic cancer, C150 significantly reduced tumor growth at the dose of 15 mg/kg by intraperitoneal injection three times per week. Furthermore, C150 enhanced protein degradation of Snail, an important EMT-promoting transcription factor, and decreased the expression of the mesenchymal marker N-cadherin, while it increased the expression of the epithelial markers zonula occludens-1 and claudin-1. The findings of the present study suggested that C150 is a novel EMT inhibitor that may be promising for inhibiting pancreatic cancer growth and metastasis.

SUBMITTER: Wang T

PROVIDER: S-EPMC8714879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Deguelin is known to suppress the growth of cancer cells; however, its anti-metastatic effects have not been studied so far in any cancer model. In the present study, we aimed to evaluate the anti-metastatic potential of deguelin in vivo and in tumor growth factor-?1 (TGF?1)-stimulated cells. Our results demonstrate that tumor growth, peritoneal dissemination and liver/lung metastasis of orthotopically implanted PanC-1-luc cells were significantly reduced in deguelin-treated mice along with the induction of apoptosis. Furthermore, deguelin-treated tumors showed increased epithelial signature such as increased expression of E-Cadherin and cytokeratin-18 and decreased expression of Snail. Similar observations were made when PanC-1, COLO-357 and L3.6pl cells were treated in vitro with deguelin. Moreover, E-cadherin was transcriptionally upregulated and accumulated in the membrane fraction of deguelin-treated cells, as indicated by increased interaction of E-Cadherin with ?-catenin. TGF?1-induced downregulation of E-Cadherin and upregulation of Snail were abrogated by deguelin treatment. In addition, deguelin inhibited TGF?1-induced Smad3 phosphorylation and Smad4 nuclear translocation in PanC-1 cells. Furthermore, when TGF?1-induced nuclear factor kappa B (NF?B) activation was inhibited, TGF?1-induced Snail upregulation or E-Cadherin downregulation was blocked. Deguelin also significantly downregulated the constitutive phosphorylation and DNA binding of NF?B in a dose-dependent manner. Interestingly, overexpression of either NF?B or Snail completely abrogated deguelin-mediated epithelial-to-mesenchymal transition (EMT) inhibition, whereas overexpression of NF?B but not Snail rescued cells from deguelin-induced apoptosis. Hence, deguelin targets NF?B to induce reversal of EMT and apoptosis but downstream effectors might be different for both processes. Taken together, our results suggest that deguelin suppresses both pancreatic tumor growth and metastasis by inducing apoptosis and inhibiting EMT.

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Novel Compound C150 Inhibits Pancreatic Cancer Cell Epithelial-to-Mesenchymal Transition and Tumor Growth in Mice.

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