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

Abstract

The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of β-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and β-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-β-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 β-catenin activity in lung cancer cells as shown by the increased β-catenin phosphorylation and activity in cells overexpressing eIF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased β-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on β-catenin activities and overexpression of β-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E- β-catenin axis. Our findings identify the eIF4E- β-catenin axis as a critical regulator of lung cancer cell growth and survival, and suggest that its pharmacological inhibition may be therapeuticallymore » useful in lung cancer. - Highlights: • Rifabutin targets EGFR-mutated lung cancer cells in vitro and in vivo. • eIF4E phosphorylation regulates β-catenin activity in lung cancer cells. • Rifabutin acts on lung cancer cells via eIF4E- β-catenin axis. • Rifabutin can be repurposed for lung cancer treatment.« less

Authors:
;  [1];  [2]; ;  [1];  [3]
  1. Department of Respiratory Medicine, Hainan General Hospital, Hainan Province (China)
  2. Equipment Division, Hainan General Hospital, Hainan Province (China)
  3. Department of Ophthalmology, Hainan Eye Hospital, ZhongShan Ophthalmic Centre, Sun Yat-Sen University, Hainan Province (China)
Publication Date:
OSTI Identifier:
22596314
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 472; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBIOTICS; APOPTOSIS; CELL CULTURES; IN VITRO; IN VIVO; INHIBITION; LUNGS; MICE; NEOPLASMS; PHOSPHORYLATION; PLANT GROWTH

Citation Formats

Li, Ji, Huang, Yijiang, Gao, Yunsuo, Wu, Haihong, Dong, Wen, and Liu, Lina. Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-β-catenin axis. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.02.120.
Li, Ji, Huang, Yijiang, Gao, Yunsuo, Wu, Haihong, Dong, Wen, & Liu, Lina. Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-β-catenin axis. United States. https://doi.org/10.1016/J.BBRC.2016.02.120
Li, Ji, Huang, Yijiang, Gao, Yunsuo, Wu, Haihong, Dong, Wen, and Liu, Lina. 2016. "Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-β-catenin axis". United States. https://doi.org/10.1016/J.BBRC.2016.02.120.
@article{osti_22596314,
title = {Antibiotic drug rifabutin is effective against lung cancer cells by targeting the eIF4E-β-catenin axis},
author = {Li, Ji and Huang, Yijiang and Gao, Yunsuo and Wu, Haihong and Dong, Wen and Liu, Lina},
abstractNote = {The essential roles of overexpression of eukaryotic translation initiation factor 4E (eIF4E) and aberrant activation of β-catenin in lung cancer development have been recently identified. However, whether there is a direct connection between eIF4E overexpression and β-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-β-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 β-catenin activity in lung cancer cells as shown by the increased β-catenin phosphorylation and activity in cells overexpressing eIF4E, and furthermore that the regulation is dependent on phosphorylation at S209. Rifabutin suppresses eIF4E phosphorylation, leads to decreased β-catenin phosphorylation and its subsequent transcriptional activities. Depletion of eIF4E abolishes the inhibitory effects of rifabutin on β-catenin activities and overexpression of β-catenin reverses the inhibitory effects of rifabutin on cell growth and survival, further confirming that rifabutin acts on lung cancer cells via targeting eIF4E- β-catenin axis. Our findings identify the eIF4E- β-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. - Highlights: • Rifabutin targets EGFR-mutated lung cancer cells in vitro and in vivo. • eIF4E phosphorylation regulates β-catenin activity in lung cancer cells. • Rifabutin acts on lung cancer cells via eIF4E- β-catenin axis. • Rifabutin can be repurposed for lung cancer treatment.},
doi = {10.1016/J.BBRC.2016.02.120},
url = {https://www.osti.gov/biblio/22596314}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 472,
place = {United States},
year = {Fri Apr 01 00:00:00 EDT 2016},
month = {Fri Apr 01 00:00:00 EDT 2016}
}