Abstract
Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents.
Highlights
We analyzed the contribution of reactive oxygen species (ROS) accumulation in the establishment of cellular senescence induced by H-RasV12 expression in normal human fibroblasts (NHF) by the use of N-acetyl-cysteine (NAC), a broad-specificity ROS scavenger that acts by replenishing cellular glutathione;[25] as a negative control, we used N-acetyl-alanine (NAA), a related but inactive compound
Given the observed interplay between NADPH oxidase (Nox)[4] and oncogenic Ras in cultured cells and in zebrafish, we investigated the role of Nox[4] in human pancreatic cancer, an aggressive tumor type typically associated with activating Ras mutations.[41]
Oncogene-induced ROS have been a complex matter in the literature and so far what has been established is limited to ROS scavenging reduces DNA damage response (DDR) and eventually commitment to cellular senescence
Summary
ROS are genotoxic but, surprisingly, by virtue of their ability to mediate oncogenedriven augmented proliferation and aberrant DNA replication This model of ROS-mediated OIS had never been proposed or demonstrated. We show for the first time that oncogene-induced ROS accumulation can be detected in a living animal Danio rerio (zebrafish), a transparent vertebrate, and preventing ROS accumulation prevents the lethal phenotype associated with oncogene activation in this animal species. We studied these events in the context of cancer.
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