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

• Published in: Oncotarget 2016-01, Vol.7 (3), p.2519-2531
• Main Authors: Liu, Fakeng, Jin, Rui, Liu, Xiuju, Huang, Henry, Wilkinson, Scott C, Zhong, Diansheng, Khuri, Fadlo R, Fu, Haian, Marcus, Adam, He, Yulong, Zhou, Wei
• Format: Article
• Language: English
• Subjects: Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Cycle; Cell Nucleus; Cell Proliferation; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Phosphorylation; Pol1 Transcription Initiation Complex Proteins - genetics; Pol1 Transcription Initiation Complex Proteins - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA Precursors - genetics; RNA Precursors - metabolism; RNA, Messenger - genetics; Transcription, Genetic; Tumor Cells, Cultured; Uridine - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6224

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-IA-mediated 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 AICAR-induced 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.