Part I—mechanism of adaptation: high nitric oxide adapted A549 cells show enhanced DNA damage response and activation of antiapoptotic pathways

Background：There are inconsistent reports about the role of Nitric Oxide (NO) in cancer progression and prevention. Quinones demonstrate significant anti-cancer activities both in vitro and in vivo. Objective： We investigated the effect of 2-methoxy-6-acetyl-7-methyljuglone (MAM), a natural naphthoquinone isolated from Polygonum cuspidatum Sieb. et Zucc, on NO generation and its role in DNA damage in cancer cells. Methods: BEL-7402 and A549 cells were cultured and treated with MAM. The NO generation, DNA damage, and protein expression were determined. Results: MAM induced inducible nitric oxide synthase (iNOS)/NO-mediated DNA damage response through activation of MAPKs pathways. MAM induced DNA damage by activating ATM/Chk2. MAM increased iNOS expression, NO production, and MAPKs (JNK1/2, ERK1/2, and p38MAPK) phosphorylation in concentrationand time- dependent manners. Furthermore, iNOS inhibitor 1400W, iNOS siRNA, and NO scavenger hemoglobin (Hb) could significantly reverse MAM-induced DNA damage, ATM/Chk2 activation, NO production, and cell death. In addition, MAPKs inhibitors (SP600125, U0126, and SB203580) reversed MAM-induced cell death and ATM/Chk2 activation. MAM-induced cell death was partially reversed by 1400W and Hb but enhanced by L-arginine. Conclusion: These results suggested that MAM induced iNOS/NO activation and generation mediated by MAPKs pathways, which resulted in DNA damage.

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2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽

10.2337/db20-2118-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2118-P

Author(s):

CHAY TENG YEO ◽

BRYNDON OLESON ◽

JOHN A. CORBETT ◽

JAMIE K. SCHNUCK

Keyword(s):

Nitric Oxide ◽

Dna Damage ◽

Dna Damage Response ◽

Ataxia Telangiectasia ◽

Damage Response

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Sulfur Mustard Analog Mechlorethamine (Bis(2-chloroethyl)methylamine) Modulates Cell Cycle Progression via the DNA Damage Response in Human Lung Epithelial A549 Cells

Chemical Research in Toxicology ◽

10.1021/acs.chemrestox.8b00417 ◽

2019 ◽

Vol 32 (6) ◽

pp. 1123-1133 ◽

Cited By ~ 7

Author(s):

Yi-Hua Jan ◽

Diane E. Heck ◽

Debra L. Laskin ◽

Jeffrey D. Laskin

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Damage Response ◽

Cell Cycle Progression ◽

Human Lung ◽

Sulfur Mustard ◽

A549 Cells ◽

Cycle Progression ◽

Lung Epithelial ◽

Damage Response

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Inhibition of DNA‑PK activity sensitizes A549 cells to X‑ray irradiation by inducing the ATM‑dependent DNA damage response

Molecular Medicine Reports ◽

10.3892/mmr.2018.8828 ◽

2018 ◽

Cited By ~ 1

Author(s):

Lina Yang ◽

Xinrui Yang ◽

Yiwei Tang ◽

Defu Zhang ◽

Lijie Zhu ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

A549 Cells ◽

X Ray ◽

Damage Response

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The DNA-Damage Response to γ-Radiation Is Affected by miR-27a in A549 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms140917881 ◽

2013 ◽

Vol 14 (9) ◽

pp. 17881-17896 ◽

Cited By ~ 26

Author(s):

Andrea Di Francesco ◽

Cristiano De Pittà ◽

Francesca Moret ◽

Vito Barbieri ◽

Lucia Celotti ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

A549 Cells ◽

Γ Radiation ◽

Damage Response

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Macrophages, Nitric Oxide and microRNAs Are Associated with DNA Damage Response Pathway and Senescence in Inflammatory Bowel Disease

PLoS ONE ◽

10.1371/journal.pone.0044156 ◽

2012 ◽

Vol 7 (9) ◽

pp. e44156 ◽

Cited By ~ 35

Author(s):

Jane J. Sohn ◽

Aaron J. Schetter ◽

Harris G. Yfantis ◽

Lisa A. Ridnour ◽

Izumi Horikawa ◽

...

Keyword(s):

Nitric Oxide ◽

Inflammatory Bowel Disease ◽

Dna Damage ◽

Dna Damage Response ◽

Bowel Disease ◽

Damage Response ◽

Inflammatory Bowel ◽

Dna Damage Response Pathway

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The Role of Metabolic Flexibility in the Regulation of the DNA Damage Response by Nitric Oxide

Molecular and Cellular Biology ◽

10.1128/mcb.00153-19 ◽

2019 ◽

Vol 39 (18) ◽

Cited By ~ 4

Author(s):

Bryndon J. Oleson ◽

Katarzyna A. Broniowska ◽

Chay Teng Yeo ◽

Michael Flancher ◽

Aaron Naatz ◽

...

Keyword(s):

Nitric Oxide ◽

Dna Damage ◽

Dna Damage Response ◽

Oxidative Metabolism ◽

Protective Mechanism ◽

Metabolic Flexibility ◽

Β Cells ◽

Β Cell ◽

Damage Response ◽

Mitochondrial Toxins

ABSTRACTIn this report, we show that nitric oxide suppresses DNA damage response (DDR) signaling in the pancreatic β-cell line INS 832/13 and rat islets by inhibiting intermediary metabolism. Nitric oxide is known to inhibit complex IV of the electron transport chain and aconitase of the Krebs cycle. Non-β cells compensate by increasing glycolytic metabolism to maintain ATP levels; however, β cells lack this metabolic flexibility, resulting in a nitric oxide-dependent decrease in ATP and NAD+. Like nitric oxide, mitochondrial toxins inhibit DDR signaling in β cells by a mechanism that is associated with a decrease in ATP. Non-β cells compensate for the effects of mitochondrial toxins with an adaptive shift to glycolytic ATP generation that allows for DDR signaling. Forcing non-β cells to derive ATP via mitochondrial respiration (replacing glucose with galactose in the medium) and glucose deprivation sensitizes these cells to nitric oxide-mediated inhibition of DDR signaling. These findings indicate that metabolic flexibility is necessary to maintain DDR signaling under conditions in which mitochondrial oxidative metabolism is inhibited and support the inhibition of oxidative metabolism (decreased ATP) as one protective mechanism by which nitric oxide attenuates DDR-dependent β-cell apoptosis.

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