PARP-1 Hyperactivation and Reciprocal Elevations in Intracellular Ca2+ During ROS-Induced Nonapoptotic Cell Death

Zhang, Fengjiao; Xie, Ruiyu; Muñoz, Frances M.; Lau, Serrine S.; Monks, Terrence J.

doi:10.1093/toxsci/kfu073

Cited by 47 publications

(29 citation statements)

References 40 publications

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“…Accumulating evidence suggests that ROS contributes to DNA damage and PARP-1 hyperactivation, the excess of which, can result in PARP-1-dependent cell death (parthanatos) 11 , 12 . Some studies have demonstrated that calcium was required for the PARP-1 hyperactivation in the model of oxidative stress-induced cell death 28 , 29 . Consistently, in our results, the production of ROS and calcium are increased in MNNG-induced parthanatos.…”

Section: Discussionmentioning

confidence: 99%

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Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro

et al. 2018

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Parthanatos is a new form of programmed cell death. It has been recognized to be critical in cerebral ischemia–reperfusion injury, and reactive oxygen species (ROS) can induce parthanatos. Recent studies found that propofol, a widely used intravenous anesthetic agent, has an inhibitory effect on ROS and has neuroprotective in many neurological diseases. However, the functional roles and mechanisms of propofol in parthanatos remain unclear. Here, we discovered that the ROS–ER–calcium–mitochondria signal pathway mediated parthanatos and the significance of propofol in parthanatos. Next, we found that ROS overproduction would cause endoplasmic reticulum (ER) calcium release, leading to mitochondria depolarization with the loss of mitochondrial membrane potential. Mitochondria depolarization caused mitochondria to release more ROS, which, in turn, contributed to parthanatos. Also, we found that propofol inhibited parthanatos through impeding ROS overproduction, calcium release from ER, and mitochondrial depolarization in parthanatos. Importantly, our results indicated that propofol protected cerebral ischemia–reperfusion via parthanatos suppression, amelioration of mitochondria, and ER swelling. Our findings provide new insights into the mechanisms of how ER and mitochondria contribute to parthanatos. Furthermore, our studies elucidated that propofol has a vital role in parthanatos prevention in vivo and in vitro, and propofol can be a promising therapeutic approach for nerve injury patients.

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Section: Discussionmentioning

confidence: 99%

“…Notably, accumulating evidence suggests that ROS has a critical role in calcium balance. Zhang et al 29 reported that intracellular calcium is required for ROS-induced PARP-1 hyperactivation in non-apoptotic cell death. Furthermore, Robert et al 30 found that mitochondrial ROS is required for elevation of cytosolic calcium.…”

Section: Discussionmentioning

confidence: 99%

Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro

et al. 2018

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“…In addition, following DNA damage, NAD + levels can drop low enough that glycolysis and substrate flux to the mitochondria is blocked leading to cell death, despite having an excess of available glucose (Alano et al, 2010; Benavente et al, 2009; Ying et al, 2005; Zhang et al, 2014). This finding highlights the need to understand the mechanisms interconnecting subcellular NAD + pools, as their homeostasis and interaction is essential for the preservation of cell viability and ATP levels.…”

Section: Introductionmentioning

confidence: 99%

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

2015

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NAD+ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD+ metabolism revived interest in NAD+ boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD+ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.

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“…Notably, cell death induced by ischemia/reperfusion shares many of the same characteristics: ROS induction, PARP1 hyperactivation, calcium release, AIF translocation, and caspase-independence. 20 , 21 Similarly, treatment with methylnitronitrosoguanidine (MNNG; a DNA alkylating agent) or induction of neuronal excitotoxicty induces PARP1 hyperactivation and cell death, but without futile cycle-induced ROS production. 22 , 23 , 24 Recent studies suggest an important role for accumulated free PAR polymer that can directly activate μ -calpain, activate and release AIF, and inhibit glycolysis.…”

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confidence: 99%

NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone

et al. 2015

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Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD+ synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD+ pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD+ consumption. Synergy with FK866+β-lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD+ synthesis while increasing NAD+ consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P)+ depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ-calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD+-Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD+ synthesis and β-lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD+ pools in cancer cells to sensitize them to ROS-mediated cell death by β-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors.

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PARP-1 Hyperactivation and Reciprocal Elevations in Intracellular Ca2+ During ROS-Induced Nonapoptotic Cell Death

Cited by 47 publications

References 40 publications

Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro

Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone

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