GDF15 Repression Contributes to 5-Fluorouracil Resistance in Human Colon Cancer by Regulating Epithelial-Mesenchymal Transition and Apoptosis

Chemotherapy based on 5-fluorouracil (5-FU) is the standard approach for colon cancer treatment, and resistance to 5-FU is a significant obstacle in the clinical treatment of colon cancer. However, the mechanisms underlying 5-FU resistance in colon cancer cells remain largely unknown. This study aimed at determining whether 5-FU-resistant colon cancer cells undergo epithelial-mesenchymal transition (EMT) and apoptosis and the role of GDF15—a member of the transforming growth factor β/bone morphogenetic protein super family and a protein known to be involved in cancer progression—in the regulation of EMT and apoptosis of these cells, along with the underlying mechanisms. In vitro apoptosis detection assay, growth inhibition assay, transwell, and wound healing experiments revealed that 5-FU-resistant colon cancer cells possessed enhanced EMT and antiapoptotic ability. These cells also showed a stronger tendency to proliferate and metastasize in vivo. Quantitative reverse transcription-PCR and western blotting revealed that 5-FU-resistant colon cancer cells expressed lower levels of growth differentiation factor 15 (GDF15) than did 5-FU-sensitive colon cancer cells. Moreover, the transient GDF15 overexpression resensitized 5-FU-resistant colon cells to 5-FU. Collectively, these findings indicate the mechanism underlying the 5-FU resistance of colon cancer cells and provide new therapeutic targets for improving the prognosis of colon cancer patients.

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Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells

Cells ◽

10.3390/cells8111343 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1343 ◽

Cited By ~ 1

Author(s):

Szeder ◽

Tárnoki-Zách ◽

Lakatos ◽

Vas ◽

Kudlik ◽

...

Keyword(s):

Colon Cancer ◽

Transcription Factors ◽

Cancer Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Cell Attachment ◽

Scaffold Protein ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Mesenchymal Transition

Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this study, the function of Tks4 was investigated in HCT116 colon cancer cells by knocking the protein out using the CRISPR/Cas9 system. Surprisingly, the absence of Tks4 induced significant changes in cell morphology, motility, adhesion and expression, and localization of E-cadherin, which are all considered as hallmarks of EMT. In agreement with these findings, the marked appearance of fibronectin, a marker of the mesenchymal phenotype, was also observed in Tks4-KO cells. Analysis of the expression of well-known EMT transcription factors revealed that Snail2 was strongly overexpressed in cells lacking Tks4. Tks4-KO cells showed increased motility and decreased cell–cell attachment. Collagen matrix invasion assays demonstrated the abundance of invasive solitary cells. Finally, the reintroduction of Tks4 protein in the Tks4-KO cells restored the expression levels of relevant key transcription factors, suggesting that the Tks4 scaffold protein has a specific and novel role in EMT regulation and cancer progression.

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Role of SPARC in the epithelial mesenchymal transition induced by PTHrP in human colon cancer cells

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2021.111253 ◽

2021 ◽

pp. 111253

Author(s):

Pedro Carriere ◽

Natalia Calvo ◽

María Belén Novoa ◽

Fernanda Lopez-Moncada ◽

Alexander Riquelme ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Mesenchymal Transition ◽

Human Colon Cancer Cells

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Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial–mesenchymal transition in human colon cancer cells

PLoS ONE ◽

10.1371/journal.pone.0205449 ◽

2018 ◽

Vol 13 (10) ◽

pp. e0205449 ◽

Cited By ~ 10

Author(s):

Sanghee Kang ◽

Bo Ram Kim ◽

Myoung-Hee Kang ◽

Dae-Young Kim ◽

Dae-Hee Lee ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Interleukin 6 ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Mesenchymal Transition ◽

Human Colon Cancer Cells

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Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through NF-κB/Snail signaling pathway

Bioscience Reports ◽

10.1042/bsr20190452 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 13

Author(s):

Jiafeng Tong ◽

Ying Shen ◽

Zhenghua Zhang ◽

Ye Hu ◽

Xu Zhang ◽

...

Keyword(s):

Colon Cancer ◽

Transcription Factors ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Colon ◽

Migration And Invasion ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Mesenchymal Transition ◽

Human Colon Cancer Cells

Abstract Colon cancer is a leading cause of cancer-related deaths worldwide. The epithelial-mesenchymal transition (EMT) plays an important role in tumor metastasis of colon cancer. We first evaluated the effects of EMT-related transcription factors on the prognosis of colon cancer through analysis the data obtained from The Cancer Genome Atlas (TCGA). And then we screened a series of Chinese medicine monomers to find effect EMT inhibitors. First, Snail is a more important EMT transcription factors for colon cancer prognosis, compared with Twist and Slug. Then, we found that apigenin effectively inhibits the activity of Snail. Apigenin could inhibit the EMT, migration, and invasion of human colon cancer cells in vitro and in vivo through the NF-κB/Snail pathway. Snail is a key regulator of EMT in colon cancer and Snail inhibitor apigenin may be a therapeutic application for patients with colon cancer.

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