Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway
| Autor: | Chun-Wai Mai, Sze-Jia See, Veronica Alicia Yap, Hsien-Chuen Soo, Yuen-Fen Tan, Tracey D. Bradshaw, Kuan-Hon Lim, Si-Hoey Tan, Chee-Onn Leong, Ling-Wei Hii, Felicia Fei-Lei Chung |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Microarrays Cell Lines Cancer Treatment Gene Expression lcsh:Medicine Apoptosis Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Signaling Medicine and Health Sciences lcsh:Science Multidisciplinary biology Cell Death Kinase Bioassays and Physiological Analysis Oncology Cell Processes 030220 oncology & carcinogenesis Biological Cultures Colorectal Neoplasms HT29 Cells Signal Transduction Research Article Signal Inhibition EGR1 Real-Time Polymerase Chain Reaction Research and Analysis Methods 03 medical and health sciences Cell Line Tumor Genetics Humans Protein kinase B PI3K/AKT/mTOR pathway Colorectal Cancer Oncogenic Signaling Phosphoinositide 3-kinase Cell growth Gene Expression Profiling lcsh:R Cancers and Neoplasms Biology and Life Sciences Cell Biology Flavones HCT116 Cells Molecular biology 030104 developmental biology P110δ biology.protein lcsh:Q Caco-2 Cells Proto-Oncogene Proteins c-akt |
| Zdroj: | PLoS ONE, Vol 12, Iss 1, p e0170551 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Cudraflavone C (Cud C) is a naturally-occurring flavonol with reported anti-proliferative activities. However, the mechanisms by which Cud C induced cytotoxicity have yet to be fully elucidated. Here, we investigated the effects of Cud C on cell proliferation, caspase activation andapoptosis induction in colorectal cancer cells (CRC). We show that Cud C inhibits cell proliferation in KM12, Caco-2, HT29, HCC2998, HCT116 and SW48 CRC but not in the non-transformed colorectal epithelial cells, CCD CoN 841. Cud C induces tumor-selective apoptosis via mitochondrial depolarization and activation of the intrinsic caspase pathway. Gene expression profiling by microarray analyses revealed that tumor suppressor genes EGR1, HUWE1 and SMG1 were significantly up-regulated while oncogenes such as MYB1, CCNB1 and GPX2 were down-regulated following treatment with Cud C. Further analyses using Connectivity Map revealed that Cud C induced a gene signature highly similar to that of protein synthesis inhibitors and phosphoinositide 3-kinase (PI3K)-AKT inhibitors, suggesting that Cud C might inhibit PI3K-AKT signaling. A luminescent cell free PI3K lipid kinase assay revealed that Cud C significantly inhibited p110β/p85α PI3K activity, followed by p120γ, p110δ/p85α, and p110α/p85α PI3K activities. The inhibition by Cud C on p110β/p85α PI3K activity was comparable to LY-294002, a known PI3K inhibitor. Cud C also inhibited phosphorylation of AKT independent of NFκB activity in CRC cells, while ectopic expression of myristoylated AKT completely abrogated the anti-proliferative effects, and apoptosis induced by Cud C in CRC. These findings demonstrate that Cud C induces tumor-selective cytotoxicity by targeting the PI3K-AKT pathway. These findings provide novel insights into the mechanism of action of Cud C, and indicate that Cud C further development of Cud C derivatives as potential therapeutic agents is warranted. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|