Abstract 4054: Elongation factor-2 kinase (eEF-2K) promotes cell invasion and epithelial mesenchymal transition through regulation of TG2-mediated signaling in human pancreatic cancer cells

Background. This study aimed to investigate the effect of propolis component caffeic acid phenethyl ester (CAPE) on epithelial-mesenchymal transition (EMT) of human pancreatic cancer cells and the molecular mechanisms underlying these effects.Methods. The transforming growth factorβ(TGF-β-) induced EMT in human pancreatic PANC-1 cancer cells was characterized by observation of morphology and the expression of E-cadherin and vimentin by western blotting. The migration potential was estimated with wound closure assay. The expression of transcriptional factors was measured by quantitative RT-PCR and immunocytochemistry staining. The orthotopic pancreatic cancer xenograft model was used forin vivoassessment.Results. The overexpression of vimentin was attenuated by CAPE, and the alteration in morphology from polygonal to spindle shape was partially reversed by CAPE. Furthermore, CAPE delayed the TGF-β-stimulated migration potential. CAPE treatment did not reduce the expression levels of Smad 2/3, Snail 1, and Zeb 1 but inhibited the expression of transcriptional factor Twist 2. By using an orthotopic pancreatic cancer model, CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity.Conclusion. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by downregulation of vimentin and Twist 2 expression.

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Inactivation of ATF‐2 enhances epithelial‐mesenchymal transition and gemcitabine sensitivity in human pancreatic cancer cells

Journal of Cellular Biochemistry ◽

10.1002/jcb.27734 ◽

2018 ◽

Vol 120 (3) ◽

pp. 4463-4471

Author(s):

Xingda Wu ◽

Zhe Liu ◽

Kejia Guo ◽

Gang Ma ◽

Shaowei Song

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Pancreatic Cancer ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

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Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1

Oncogene ◽

10.1038/s41388-020-01423-8 ◽

2020 ◽

Vol 39 (39) ◽

pp. 6218-6230 ◽

Cited By ~ 2

Author(s):

Akane Kanamori ◽

Daisuke Matsubara ◽

Yurika Saitoh ◽

Yuya Fukui ◽

Noriko Gotoh ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Hypoxia Inducible Factor ◽

Human Pancreatic Cancer ◽

Mesenchymal Transition ◽

Skp2 Expression ◽

Pancreatic Cancer Cells

Abstract Pancreatic cancer is one of the most fatal cancers without druggable molecular targets. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional factor that promotes malignancy in various cancers including pancreatic cancer. Herein, we found that HIF-1 is accumulated in normoxic or moderate hypoxic areas of pancreatic cancer xenografts in vivo and is active even during normoxia in pancreatic cancer cells in vitro. This prompted us to analyze whether the HIF-1 activator Mint3 contributes to malignant features of pancreatic cancer. Mint3 depletion by shRNAs attenuated HIF-1 activity during normoxia and cell proliferation concomitantly with accumulated p21 and p27 protein in pancreatic cancer cells. Further analyses revealed that Mint3 increased transcription of the oncogenic ubiquitin ligase SKP2 in pancreatic cancer cells via HIF-1. This Mint3-HIF-1-SKP2 axis also promoted partial epithelial-mesenchymal transition, stemness features, and chemoresistance in pancreatic cancer cells. Even in vivo, Mint3 depletion attenuated tumor growth of orthotopically inoculated human pancreatic cancer AsPC-1 cells. Database and tissue microarray analyses showed that Mint3 expression is correlated with SKP2 expression in human pancreatic cancer specimens and high Mint3 expression is correlated with poor prognosis of pancreatic cancer patients. Thus, targeting Mint3 may be useful for attenuating the malignant features of pancreatic cancer.

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