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Author Notes:

Correspondence to: Wei Zhou, email: wzhou2@emory.edu.

Conception and design: F. Liu, R. Jin, W. Zhou.

Development of methodology: F. Liu, R. Jin, X. Liu, H. Huang, SC Wilkinson, D. Zhong.

Acquisition of data: F. Liu, R. Jin, X. Liu, H, Huang, D. Zhong, F. Khuri, H, Fu, A.I. Marcus, W. Zhou.

Analysis and interpretation of data; F. Liu, J. Rui, H. Fu, AI. Marcus, F. Khuri, Y. He, W. Zhou.

Writing, review, and/or revision of the manuscript: F. Liu, R. Jin, H Fu, Y. He, A. Marcus, F. Khuri, and W. Zhou.

Study supervision: W. Zhou.

We would like to thank Dr. Anthea Hammond for editing this manuscript and Drs. DePinho and Viollet for providing LKB1-null and AMPK-null MEF cells.

WZ, FRK and AIM are Georgia Cancer Coalition Distinguished Cancer Scholars. WZ is an Anise McDaniel Brock Scholar and an American Cancer Society Research Scholar.

The authors declare no conflict of interest.


Research Funding:

This work was supported in part by R01-CA140571 to WZ, P01 CA116676 to FRK, China Scholarship Council to FL, R01CA142858 to AIM, National Science Foundation Graduate Research Fellowship DGE-0940903 to SW, P30CA138292 to Winship Cancer Institute, and Anise McDaniel Brock Scholar fund to WZ.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • pre-ribosomal RNA synthesis
  • TIF-IA
  • serine/threonine kinase 11
  • targeted therapy
  • tumor suppressor

LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions

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Journal Title:



Volume 7, Number 3


, Pages 2519-2531

Type of Work:

Article | Final Publisher PDF


We analyzed the mechanism underlying 5-aminoimidazole-4-carboxamide riboside (AICAR) mediated apoptosis in LKB1-null non-small cell lung cancer (NSCLC) cells. Metabolic profile analysis revealed depletion of the intracellular pyrimidine pool after AICAR treatment, but uridine was the only nucleotide precursor capable of rescuing this apoptosis, suggesting the involvement of RNA metabolism. Because half of RNA transcription in cancer is for pre-ribosomal RNA (rRNA) synthesis, which is suppressed by over 90% after AICAR treatment, we evaluated the role of TIF-IAmediated rRNA synthesis. While the depletion of TIF-IA by RNAi alone promoted apoptosis in LKB1-null cells, the overexpression of a wild-type or a S636A TIF-IA mutant, but not a S636D mutant, attenuated AICAR-induced apoptosis. In LKB1-null H157 cells, pre-rRNA synthesis was not suppressed by AICAR when wild-type LKB1 was present, and cellular fractionation analysis indicated that TIF-IA quickly accumulated in the nucleus in the presence of a wild-type LKB1 but not a kinase-dead mutant. Furthermore, ectopic expression of LKB1 was capable of attenuating AICARinduced death in AMPK-null cells. Because LKB1 promotes cell survival by modulating TIF-IA-mediated pre-rRNA synthesis, this discovery suggested that targeted depletion of uridine related metabolites may be exploited in the clinic to eliminate LKB1-null cancer cells.

Copyright information:

© 2016 Liu et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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