Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway.

Abstract

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.

• Authors: Hsien-Chuen Soo, Felicia Fei-Lei Chung, Kuan-Hon Lim, Veronica Alicia Yap, Tracey D Bradshaw, Ling-Wei Hii, Si-Hoey Tan, Sze-Jia See, Yuen-Fen Tan, Chee-Onn Leong, Chun-Wai Mai
• Journal: PloS one (PLoS One) Vol. 12 Issue 1 Pg. e0170551 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28107519 (Publication Type: Journal Article)

Chemical References

• Flavones
• cudraflavone C
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Apoptosis (drug effects)
• Caco-2 Cells
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy)
• Flavones (pharmacology)
• Gene Expression Profiling
• HCT116 Cells
• HT29 Cells
• Humans
• Phosphatidylinositol 3-Kinases (drug effects)
• Proto-Oncogene Proteins c-akt (drug effects)
• Real-Time Polymerase Chain Reaction
• Signal Transduction (drug effects)