Ultrafast Vibrational Wave Packet Dynamics of the Aqueous Guanine Radical Anion Induced by Photodetachment

Studying the ultrafast dynamics of ionized aqueous biomolecules is important for gaining an understanding of the interaction of ionizing radiation with biological matter. Guanine plays an essential role in biological systems as one of the four nucleobases that form the building blocks of deoxyribonucleic acid (DNA). Guanine radicals can induce oxidative damage to DNA, particularly due to the lower ionization potential of guanine compared to the other nucleobases, sugars, and phosphate groups that are constituents of DNA. This study utilizes femtosecond optical pump–probe spectroscopy to observe the ultrafast vibrational wave packet dynamics of the guanine radical anion launched by photodetachment of the aqueous guanine dianion. The vibrational wave packet motion is resolved into 11 vibrational modes along which structural reorganization occurs upon photodetachment. These vibrational modes are assigned with the aid of density functional theory (DFT) calculations. Our work sheds light on the ultrafast vibrational dynamics following the ionization of nucleobases in an aqueous medium

table_1_Inhibiting Glycine Decarboxylase Suppresses Pyruvate-to-Lactate Metabolism in Lung Cancer Cells.docx

<p>Glycine decarboxylase (GLDC) gene is frequently upregulated in various types of cancer including lung, prostate and brain. It catabolizes glycine to yield 5,10-methylenetetrahydrofolate, an important substrate in one-carbon metabolism for nucleotide synthesis. In this study, we used exon splicing modulating steric hindrance antisense oligonucleotide (shAON) to suppress GLDC expression and investigated its effect on pyruvate metabolism via hyperpolarized carbon-13 magnetic resonance spectroscopy (MRS). The MRS technique allows us to study in vivo metabolic flux in tumor tissues with/without GLDC-shAON intervention. Here, we show that GLDC-shAON treatment is able to suppress lung cancer cell growth and tumorigenesis, both in vitro and in vivo. The carbon-13 MRS results indicated that the conversion of pyruvate into lactate in GLDC-shAON-treated tumor tissues was significantly reduced, when compared with the control groups. This observation corroborated with the reduced activity of lactate dehydrogenase and pyruvate dehydrogenase in GLDC-shAON-treated lung cancer cells and tumor tissues. Glycolysis stress test showed that extracellular acidification rate was significantly suppressed after GLDC-shAON treatment. Besides lung cancer, the antitumor effect of GLDC-shAON was also observed in brain, liver, cervical, and prostate cancer cell lines. Furthermore, it enhanced the treatment efficacy of cisplatin in lung cancer cells. Taken together, our findings illustrate that pyruvate metabolism decreases upon GLDC inhibition, thereby starving cancer cells from critical metabolic fuels.</p

image_1_Inhibiting Glycine Decarboxylase Suppresses Pyruvate-to-Lactate Metabolism in Lung Cancer Cells.tif

<p>Glycine decarboxylase (GLDC) gene is frequently upregulated in various types of cancer including lung, prostate and brain. It catabolizes glycine to yield 5,10-methylenetetrahydrofolate, an important substrate in one-carbon metabolism for nucleotide synthesis. In this study, we used exon splicing modulating steric hindrance antisense oligonucleotide (shAON) to suppress GLDC expression and investigated its effect on pyruvate metabolism via hyperpolarized carbon-13 magnetic resonance spectroscopy (MRS). The MRS technique allows us to study in vivo metabolic flux in tumor tissues with/without GLDC-shAON intervention. Here, we show that GLDC-shAON treatment is able to suppress lung cancer cell growth and tumorigenesis, both in vitro and in vivo. The carbon-13 MRS results indicated that the conversion of pyruvate into lactate in GLDC-shAON-treated tumor tissues was significantly reduced, when compared with the control groups. This observation corroborated with the reduced activity of lactate dehydrogenase and pyruvate dehydrogenase in GLDC-shAON-treated lung cancer cells and tumor tissues. Glycolysis stress test showed that extracellular acidification rate was significantly suppressed after GLDC-shAON treatment. Besides lung cancer, the antitumor effect of GLDC-shAON was also observed in brain, liver, cervical, and prostate cancer cell lines. Furthermore, it enhanced the treatment efficacy of cisplatin in lung cancer cells. Taken together, our findings illustrate that pyruvate metabolism decreases upon GLDC inhibition, thereby starving cancer cells from critical metabolic fuels.</p