LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions.
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.
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.|Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
Fakeng
F
Liu
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Rui
R
Jin
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Xiuju
X
Liu
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Henry
H
Huang
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.|Graduate Program in Cancer Biology, Emory University, Atlanta, GA, USA.
Scott C
SC
Wilkinson
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.|Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, P.R.China.
Diansheng
D
Zhong
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Fadlo R
FR
Khuri
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Haian
H
Fu
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Adam
A
Marcus
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
Yulong
Y
He
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.|Department of Pathology and Laboratory Medicine and Department of Human Genetics Emory University School of Medicine, Atlanta, GA, USA.
Wei
W
Zhou
D000091162:AMP-Activated Protein Kinase Kinases; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D002467:Cell Nucleus; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000378:metabolism*
D035463:Pol1 Transcription Initiation Complex Proteins; D012322:RNA Precursors; D012333:RNA, Messenger; C428423:RRN3 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D014529:Uridine
TIF-IA; pre-ribosomal RNA synthesis; serine/threonine kinase 11; targeted therapy; tumor suppressor