Abstract
Background: Cancer cells from solid tumors become metabolically stressed, when nutrients are insufficient within poorly vascularized regions. Metabolic stress resulting from severe deprivation of glucose and serum-derived growth factors can promote cell death, partly through excessive reactive oxygen species (ROS) production. As possible sources of oxidative stress, NADPH oxidases (NOX) are centrally involved in the control of the malignant state: activated NOX enzymes use NADPH as an electron donor to reduce molecular oxygen generating superoxide anion radical (O2•−), which can act extracellularly as an autocrine/paracrine regulator or intracellularly as a signaling messenger in a variety of mammalian cells. Excessive superoxide can be dismutated to H2O2. by superoxide dismutases (SOD). Objectives: To investigate whether chemical inhibition of NOX or removal of extracellular superoxide by exogenous SOD influences tumor cell survival depending on p53 status or metabolic stress. Experimental: Genetically-matched human melanoma cells with unequal p53 mutational status were exposed to glucose or serum starvation under normoxia, physical hypoxia and/or chemical hypoxia .Differential cell survival was assesed by live-dead fluorometric assays or crystal violet staining. Mechanisms influencing response to glucose limitation were studied by specific immune blotting. Results: Lower cell proliferation under normoxia in 1 % serum was attenuated by chemically or enzymatically decreasing superoxide or by exposing them to hypoxia. Diphenylene iodonium preferentially restored the metabolic activity of mutant p53 cells in 1 % serum, whereas SOD acted preferentially on wt p53 cells under comparable conditions.
Apoptosis-associated PARP cleavage under normoxia in 2.5 mM glucose and 5 % dialyzed serum was counteracted by SOD only in wt p53 cells. Cell death induced by CoCl2 preconditioning in the absence of physical hypoxia was preferential for mut p53 C8161 melanoma and reversed by SOD. Conclusions: Our results support a cytotoxic role for Nox-mediated free radical production in cancer cell death under metabolic stress, and suggests that p53 mutation increases superoxide-mediated toxicity during limitation of intracellular glucose and/ serum-derived growth factors.
Citation Format: Valery Chavez-Perez, Mary Strasberg-Rieber, Manuel Rieber. Superoxide modulates tumor cell survival in response to hypoxia and metabolic stress: role of p53 status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1890. doi:10.1158/1538-7445.AM2013-1890
