Cytoplasmic Irradiation Induces Metabolic Shift in Human Small Airway Epithelial Cells via Activation of Pim-1 Kinase.
The unique cellular and molecular consequences of cytoplasmic damage caused by ionizing radiation were studied using a precision microbeam irradiator. Our results indicated that targeted cytoplasmic irradiation induced metabolic shift from an oxidative to glycolytic phenotype in human small airway epithelial cells (SAE). At 24 h postirradiation, there was an increase in the mRNA expression level of key glycolytic enzymes as well as lactate secretion in SAE cells. Using RNA-sequencing analysis to compare genes that were responsive to cytoplasmic versus nuclear irradiation, we found a glycolysis related gene, Pim-1, was significantly upregulated only in cytoplasmic irradiated SAE cells. Inhibition of Pim-1 activity using the selective pharmaceutic inhibitor Smi-4a significantly reduced the level of lactate production and glucose uptake after cytoplasmic irradiation. In addition, Pim-1 also inhibited AMPK activity, which is a well-characterized negative regulator of glycolysis. Distinct from the glycolysis induced by cytoplasmic irradiation, targeted nuclear irradiation also induced a transient and minimal increase in glycolysis that correlated with increased expression of Hif-1α. In an effort to explore the underline mechanism, we found that inhibition of mitochondria fission using the cell-permeable inhibitor mdivi-1 suppressed the induction of Pim-1, thus confirming Pim-1 upregulation as a downstream effect of mitochondrial dysfunction. Our data show and, for the first time, that cytoplasmic irradiation mediate expression level of Pim-1, which lead to glycolytic shift in SAE cells. Additionally, since glycolysis is frequently linked to cancer cell metabolism, our findings further suggest a role of cytoplasmic damage in promoting neoplastic changes.
a   Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032.|d   Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui, China 230031.
Jinhua
J
Wu
c   Department of Environmental Health and Occupational Medicine, West China School of Public Health, Sichuan University. Chengdu, Sichuan, China 610041; and.
Qin
Q
Zhang
a   Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032.
Yen-Ruh
YR
Wuu
a   Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032.
Sirui
S
Zou
a   Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York 10032.|b   Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032.
Tom K
TK
Hei
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001483:Base Sequence / Q000528:radiation effects; D002460:Cell Line; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D004789:Enzyme Activation / Q000528:radiation effects; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects*; D006019:Glycolysis / Q000528:radiation effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000528:radiation effects; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects*; D015854:Up-Regulation / Q000528:radiation effects
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012313:RNA; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D055372:AMP-Activated Protein Kinases