scholarly journals Withdrawal: Transforming growth factor β mediates drug resistance by regulating the expression of pyruvate dehydrogenase kinase 4 in colorectal cancer.

2020 ◽  
Vol 295 (13) ◽  
pp. 4368-4368
Author(s):  
Yang Zhang ◽  
Yi Zhang ◽  
Liying Geng ◽  
Haowei Yi ◽  
Wei Huo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Growth Factor ◽  
Pyruvate Dehydrogenase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Pyruvate Dehydrogenase Kinase ◽  
Pyruvate Dehydrogenase Kinase 4

scholarly journals Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

2016 ◽  
Vol 291 (33) ◽  
pp. 17405-17416 ◽  
Author(s):  
Yang Zhang ◽  
Yi Zhang ◽  
Liying Geng ◽  
Haowei Yi ◽  
Wei Huo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Mouse Xenograft Model

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

scholarly journals Human Colorectal Cancer from the Perspective of Mouse Models

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 788 ◽  
Author(s):  
Monika Stastna ◽  
Lucie Janeckova ◽  
Dusan Hrckulak ◽  
Vitezslav Kriz ◽  
Vladimir Korinek
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Mouse Models ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Molecular Subtype ◽  
Transforming Growth Factor Β ◽  
Dna Mismatch ◽  
Individual Mouse ◽  
Consensus Molecular Subtype

Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.

A Colorectal Cancer Expression Profile That Includes Transforming Growth Factor β Inhibitor BAMBI Predicts Metastatic Potential

2009 ◽  
Vol 137 (1) ◽  
pp. 165-175 ◽  
Author(s):  
Johannes Fritzmann ◽  
Markus Morkel ◽  
Daniel Besser ◽  
Jan Budczies ◽  
Frauke Kosel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Expression Profile ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Metastatic Potential

An In Silico Investigation of Potential EGFR Inhibitors for the Clinical Treatment of Colorectal Cancer

2019 ◽  
Vol 18 (27) ◽  
pp. 2355-2366 ◽  
Author(s):  
Manisha Majhi ◽  
Meer Asif Ali ◽  
Akanksha Limaye ◽  
Kritika Sinha ◽  
Praveena Bairagi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Docking ◽  
Growth Factor ◽  
Virtual Screening ◽  
Transforming Growth Factor ◽  
Transmembrane Protein ◽  
Protein A ◽  
Growth Factor Receptor ◽  
Transforming Growth Factor Β ◽  
Egfr Inhibitors

Colorectal cancer possesses the third highest diagnostic rate and is the second leading cause of cancer death in the USA as reported by NIH. Epidermal Growth Factor Receptor (EGFR), a transmembrane protein, participates in PLC gamma-1, RAS-RAF-MEK-MAPKs, phosphatidylinositol-3 kinase, Akt pathways and plays a key role in normal functioning of cell division, cell differentiation, apoptosis and migration. This protein is found to be overexpressed in more than 60% of the colorectal cancers. Overexpressed EGFR advances the tumorigenic properties through cell cycle dysregulation and activates signaling pathways linked to cancer such as WNT/β-catenin, transforming growth factor β (TGF-β) and phosphoinositide-3-kinase (PI3K). Inhibiting the overexpressed EGFR protein has been proposed for the treatment and many inhibitors have been reported suppressing the activity of EGFR. However, patients in malignant state of cancer show resistance to those inhibitors, which open a wide space to research for the discovery of novel inhibitors. The present study employed Molecular Docking and Virtual Screening to find novel inhibitors with high affinity against EGFR. Molecular docking of existing inhibitors resulted in the compound titled as BGB-283 (PubChem CID-89670174) having the highest score, which was subjected to similarity search to retrieve the drugs with similar structure. The virtual screening concluded a compound SCHEMBL18435602 (PubChem CID-126517400) which revealed a better affinity with the target protein. A comparative study of both the compounds showed equivalent pharmacokinetic properties. These identified drugs have a high potential to act as EGFR inhibitors and can show promising results in the research of colorectal cancer.

scholarly journals Transforming Growth Factor β Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2

2015 ◽  
Vol 148 (7) ◽  
pp. 1427-1437.e8 ◽  
Author(s):  
Noel F.C.C. de Miranda ◽  
Maarten van Dinther ◽  
Brendy E.W.M. van den Akker ◽  
Tom van Wezel ◽  
Peter ten Dijke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Microsatellite Instability ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Colorectal Cancer Cells ◽  
Biallelic Mutations
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