Rhamnetin and cirsiliol induce radiosensitization and inhibition of epithelial-mesenchymal transition (EMT) by miR-34a-mediated suppression of Notch-1 expression in non-small cell lung cancer cell lines.

Abstract

Radioresistance is a major cause of decreasing the efficiency of radiotherapy for non-small cell lung cancer (NSCLC). To understand the radioresistance mechanisms in NSCLC, we focused on the radiation-induced Notch-1 signaling pathway involved in critical cell fate decisions by modulating cell proliferation. In this study, we investigated the use of Notch-1-regulating flavonoid compounds as novel therapeutic drugs to regulate radiosensitivity in NSCLC cells, NCI-H1299 and NCI-H460, with different levels of radioresistance. Rhamnetin and cirsiliol were selected as candidate Notch-1-regulating radiosensitizers based on the results of assay screening for activity and pharmacological properties. Treatment with rhamnetin or cirsiliol reduced the proliferation of NSCLC cells through the suppression of radiation-induced Notch-1 expression. Indeed, rhamnetin and cirsiliol increased the expression of tumor-suppressive microRNA, miR-34a, in a p53-dependent manner, leading to inhibition of Notch-1 expression. Consequently, reduced Notch-1 expression promoted apoptosis through significant down-regulation of the nuclear factor-κB pathway, resulting in a radiosensitizing effect on NSCLC cells. Irradiation-induced epithelial-mesenchymal transition was also notably attenuated in the presence of rhamnetin and cirsiliol. Moreover, an in vivo xenograft mouse model confirmed the radiosensitizing and epithelial-mesenchymal transition inhibition effects of rhamnetin and cirsiliol we observed in vitro. In these mice, tumor volume was significantly reduced by combinational treatment with irradiation and rhamnetin or cirsiliol compared with irradiation alone. Taken together, our findings provided evidence that rhamnetin and cirsiliol can act as promising radiosensitizers that enhance the radiotherapeutic efficacy by inhibiting radiation-induced Notch-1 signaling associated with radioresistance possibly via miR-34a-mediated pathways.

• Authors: JiHoon Kang, EunGi Kim, Wanyeon Kim, Ki Moon Seong, HyeSook Youn, Jung Woo Kim, Joon Kim, BuHyun Youn
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 38 Pg. 27343-27357 (Sep 20 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23902763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Flavones
• MIRN34 microRNA, human
• MicroRNAs
• NF-kappa B
• NOTCH1 protein, human
• RNA, Neoplasm
• Receptor, Notch1
• TP53 protein, human
• Tumor Suppressor Protein p53
• cirsiliol
• rhamnetin
• Quercetin

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology, therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects, radiation effects)
• Epithelial-Mesenchymal Transition (drug effects, radiation effects)
• Flavones (pharmacology)
• Gamma Rays
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Humans
• Lung Neoplasms (metabolism, pathology, therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (biosynthesis)
• NF-kappa B (metabolism)
• Quercetin (analogs & derivatives, pharmacology)
• RNA, Neoplasm (biosynthesis)
• Radiation Tolerance (drug effects, radiation effects)
• Receptor, Notch1 (biosynthesis)
• Tumor Suppressor Protein p53 (metabolism)