Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-beta-catenin axis

作者：Li, Ji; Huang, Yijiang; Gao, Yunsuo; Wu, Haihong; Dong, Wen; Liu, Lina^*

来源：Biochemical and Biophysical Research Communications, 2016, 472(2): 299-305.

DOI：10.1016/j.bbrc.2016.02.120

• Rifabutin
• eIF4E
• beta-catenin
• Lung cancer
• Drug repositioning

The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of P-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and beta-catenin activation in lung cancer cells is unknown. In this study, we show that antibiotic drug rifabutin targets human lung cancer cells via inhibition of eIF4E-beta-catenin axis. Rifabutin is effectively against lung cancer cells in in vitro cultured cells and in vivo xenograft mouse model through inhibiting proliferation and inducing apoptosis. Mechanistically, eIF4E regulates D-catenin activity in lung cancer cells as shown by the increased beta-catenin phosphorylation and activity in cells overexpressing elF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased beta-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on P-catenin activities and overexpression of beta-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E-beta-catenin axis. Our findings identify the eIF4E-beta-catenin axis as a critical regulator of lung cancer cell growth and survival, and suggest that its pharmacological inhibition may be therapeutically useful in lung cancer.

• 出版日期2016-4-1
• 单位中山大学