Rithika Venkatesh - Academia.edu (original) (raw)
Papers by Rithika Venkatesh
Free Radical Biology and Medicine, 2013
Although reactive oxygen species (ROS) are well-established mediators of oxidative damage and cel... more Although reactive oxygen species (ROS) are well-established mediators of oxidative damage and cell demise, the mechanisms by which they trigger specific cell death modalities and the temporal/spatial requirements underlying this phenomenon are largely unknown. Yet, it is well established that most anticancer therapies depend on ROS production for efficient tumor eradication. Using several non-small-cell lung cancer cell lines, we have dissected how the site of ROS production and accumulation in various cell compartments affect cell fate. We demonstrate that high levels of exogenously generated H2O2 induce extensive DNA damage, ATP depletion, and severe cytotoxicity. Although these effects were independent of caspase activity, they could-at least in part-be prevented by RIP1 kinase inhibition. In contrast, low levels of exogenously produced H2O2 triggered a modest drop in ATP level, delayed toxicity, G2/M arrest, and cell senescence. Mitochondrially produced H2O2 induced a reversible ATP drop without affecting cell viability. Instead, the cells accumulated in the G1/S phase of the cell cycle and became senescent. Concomitant inhibition of glycolysis was found to markedly sensitize cells to death in the presence of otherwise nontoxic concentrations of H2O2, presumably by the inhibition of ATP-restoring mechanisms. Combined, our data provide evidence that ROS might dictate different cellular consequences depending on their overall concentration at steady-state levels and on their site of generation.
Aging Cell, 2011
Abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in... more Abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro-oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor-b (TGF-b) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor-a (TNF-a) signaling via NF-jB and NADPH oxidase. Aged Mstn null (Mstn ) ⁄ ) ) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF-jB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF-a and hydrogen peroxide (H 2 O 2 ) are potent inducers of Mstn and require NF-jB signaling for Mstn induction. These results demonstrate that Mstn and TNF-a are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF-a and NADPH oxidase, and the elevated TNF-a in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal-mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia.
Free Radical Biology and Medicine, 2013
Although reactive oxygen species (ROS) are well-established mediators of oxidative damage and cel... more Although reactive oxygen species (ROS) are well-established mediators of oxidative damage and cell demise, the mechanisms by which they trigger specific cell death modalities and the temporal/spatial requirements underlying this phenomenon are largely unknown. Yet, it is well established that most anticancer therapies depend on ROS production for efficient tumor eradication. Using several non-small-cell lung cancer cell lines, we have dissected how the site of ROS production and accumulation in various cell compartments affect cell fate. We demonstrate that high levels of exogenously generated H2O2 induce extensive DNA damage, ATP depletion, and severe cytotoxicity. Although these effects were independent of caspase activity, they could-at least in part-be prevented by RIP1 kinase inhibition. In contrast, low levels of exogenously produced H2O2 triggered a modest drop in ATP level, delayed toxicity, G2/M arrest, and cell senescence. Mitochondrially produced H2O2 induced a reversible ATP drop without affecting cell viability. Instead, the cells accumulated in the G1/S phase of the cell cycle and became senescent. Concomitant inhibition of glycolysis was found to markedly sensitize cells to death in the presence of otherwise nontoxic concentrations of H2O2, presumably by the inhibition of ATP-restoring mechanisms. Combined, our data provide evidence that ROS might dictate different cellular consequences depending on their overall concentration at steady-state levels and on their site of generation.
Aging Cell, 2011
Abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in... more Abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro-oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor-b (TGF-b) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor-a (TNF-a) signaling via NF-jB and NADPH oxidase. Aged Mstn null (Mstn ) ⁄ ) ) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF-jB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF-a and hydrogen peroxide (H 2 O 2 ) are potent inducers of Mstn and require NF-jB signaling for Mstn induction. These results demonstrate that Mstn and TNF-a are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF-a and NADPH oxidase, and the elevated TNF-a in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal-mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia.