Radiation induces senescence and a bystander effect through metabolic alterations.
Cellular senescence is a state of irreversible growth arrest; however, the metabolic processes of senescent cells remain active. Our previous studies have shown that radiation induces senescence of human breast cancer cells that display low expression of securin, a protein involved in control of the metaphase-anaphase transition and anaphase onset. In this study, the protein expression profile of senescent cells was resolved by two-dimensional gel electrophoresis to investigate associated metabolic alterations. We found that radiation induced the expression and activation of glyceraldehyde-3-phosphate dehydrogenase that has an important role in glycolysis. The activity of lactate dehydrogenase A, which is involved in the conversion of pyruvate to lactate, the release of lactate and the acidification of the extracellular environment, was also induced. Inhibition of glycolysis by dichloroacetate attenuated radiation-induced senescence. In addition, radiation also induced activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor kappa B (NF-κB) pathways to promote senescence. We also found that radiation increased the expression of monocarboxylate transporter 1 (MCT1) that facilitates the export of lactate into the extracellular environment. Inhibition of glycolysis or the AMPK/NF-κB signalling pathways reduced MCT1 expression and rescued the acidification of the extracellular environment. Interestingly, these metabolic-altering signalling pathways were also involved in radiation-induced invasion of the surrounding, non-irradiated breast cancer and normal endothelial cells. Taken together, radiation can induce the senescence of human breast cancer cells through metabolic alterations.
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
E-C
EC
Liao
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
Y-T
YT
Hsu
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
Q-Y
QY
Chuah
Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
Y-J
YJ
Lee
Department of Life Sciences, Tzu Chi University, Hualien, Taiwan.
J-Y
JY
Hu
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
T-C
TC
Huang
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
P-M
0000000240042518
PM
Yang
1] Department of Life Sciences, Tzu Chi University, Hualien, Taiwan [2] Institute of Radiological Sciences, Tzu Chi Technology College, Hualien, Taiwan.
S-J
SJ
Chiu
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024201:Bystander Effect; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects*; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis / Q000528:radiation effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D064249:Securin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D027981:Symporters / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000099233:Monocarboxylate Transport Protein 1
D055372:AMP-Activated Protein Kinases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D027501:Monocarboxylic Acid Transporters; D016328:NF-kappa B; D064249:Securin; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C578002:pituitary tumor-transforming protein 1, human