Genotype-Dependent Tumor Inhibitory Effects of Metformin in Glioblastoma Cells

Zhang, C.; Zhou, Hongning; Chao, K.; Hei, T.K.

doi:10.1016/j.ijrobp.2014.05.2304

Cited by 1 publication

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“…Our previous results suggested a unique role of mitochondrial fission induced by cytoplasmic irradiation in mediating cellular responses including autophagy and apoptosis (33), therefore we tested the potential involvement of mitochondrial fission in regulating glycolysis. By inhibiting cytoplasmic irradiation induced mitochondrial fission using pharmaceutic inhibitor mdivi-1, we observed strong suppression of cytoplasmic irradiation induced Pim-1expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic Irradiation Induces Metabolic Shift in Human Small Airway Epithelial Cells via Activation of Pim-1 Kinase

Zhang

Wuu

et al. 2017

Radiation Research

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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.

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Section: Resultsmentioning

confidence: 99%