Targeted Modulation of FAK/PI3K/PDK1/AKT and FAK/p53 Pathways by Cucurbitacin B for the Antiproliferation Effect Against Human Cholangiocarcinoma Cells
| Autor: | Auemduan Prawan, Laddawan Senggunprai, Veerapol Kukongviriyapan, Sirinapha Klungsaeng, Sarinya Kongpetch |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
CDC25A Receptor ErbB-2 Cyclin A Gene Expression Receptor tyrosine kinase Cholangiocarcinoma 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Cyclin D1 Cell Line Tumor Humans Molecular Targeted Therapy Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation biology Chemistry Cell growth Pyruvate Dehydrogenase Acetyl-Transferring Kinase General Medicine Cell cycle Triterpenes ErbB Receptors 030104 developmental biology Complementary and alternative medicine Bile Duct Neoplasms 030220 oncology & carcinogenesis Focal Adhesion Protein-Tyrosine Kinases Cancer research biology.protein Tumor Suppressor Protein p53 Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The American journal of Chinese medicine. 48(6) |
| ISSN: | 1793-6853 |
| Popis: | Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein. |
| Databáze: | OpenAIRE |
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