oncogenes are mutated forms of cellular genes that are responsible for driving rampant cellular proliferation .
however , the expression of an activated oncogene in normal human cells does not lead to their transformation , but to a permanent cell cycle arrest known as cellular senescence .
hence , oncogene - induced senescence ( ois ) serves as a tumor suppressor mechanism that restricts the progression of pre - neoplastic lesions .
the role of oncogene - induced reactive oxygen species ( ros ) production in cancer development has been a controversial subject .
ros is a collective term describing a number of highly reactive molecules and free radicals that are formed upon incomplete reduction of oxygen .
ros can either directly damage or modulate redox - sensitive signaling pathways , depending on the molecular concentrations at which they are present . in particular , the role of oncogenic ras - regulated ros production in cellular transformation has been the subject of several studies .
nonetheless , it remains unclear whether oncogenic ros have a direct role in genome instability and , if so , which molecular mechanisms are involved .
we approached this issue by taking a closer look at the mode of action of oncogene - induced ros in the model system of h - ras oncogenic activation in normal human fibroblasts .
we observed that removal of ros by the broad specificity scavenger n - acetyl cysteine ( nac ) inhibits oncogene - induced hyperproliferation , prevents activation of the dna damage response ( ddr ) , and reduces the establishment of senescence .
this experiment led us to propose the novel concept that oncogene - induced ros are modulators of cell hyperproliferation that engage the ddr by exposing cells to dna replication stress .
we then focused on the origins of the oncogene - induced ros , which are ubiquitously generated through diverse enzymatic pathways .
in particular , we turned our attention to the nox family of oxidases because initial studies suggested them as a source of ros in cancer .
our experiments identified the ras - rac1-nox4 axis as the pathway responsible for ros generation by oncogenic ras in human cells .
therefore , we propose that ras - induced ros are mitogenic signaling molecules for the initial hyperproliferative phase , which is causally associated with the altered dna replication that precedes and prompts ddr activation and ultimately leads to senescence .
cell transformation is associated with bypass of ois and ongoing rampant proliferation . since oncogene activation hijacks the ros - modulated proliferative cues for the initial hyperproliferative phase , we investigated the effect of ros scavengers and nox4 inhibitors on proliferating cells .
these cells either harbor mutations to bypass ois or are fully transformed , and either express oncogenic ras or do not .
we observed that the expression of oncogenic ras in a cell is sufficient to confer sensitivity to ros manipulations .
we also treated cells derived from human pancreatic cancer with gemcitabine , the standard of care chemotherapy treatment for pancreatic cancer , and nox4 inhibitors .
although we observed a modest effect of nox4 inhibitors alone , we discovered an exciting synergic effect of nox4 inhibitors and gemcitabine that reduced the half - maximal inhibitory concentration ( ic50 ) of this nucleoside analog by up to 6-fold .
deregulation of survival pathways by nox - derived ros through jak , stat , akt , and nfb pathways has been previously implicated ; however , the mechanism by which combined use of nox4 inhibitors and gemcitabine enhances apoptosis in cancer cells remains unclear .
using a well - established mouse model of ras - induced pancreatic cancer , we reported increased induction of nox4 during progression from the earliest neoplastic lesions to more invasive ones . in addition , we observed robust nox4 expression in a set of human pancreatic tumors , with signal intensity correlating with neoplastic stage .
importantly , and concordant with our results in cultured cells , nox4 levels in these human lesions correlated with markers of ddr activation .
cancer cells produce elevated levels of ros and exhibit altered metabolic pathways and regulatory mechanisms in order to maintain redox balance .
therefore , high levels of ros production are counterbalanced by an equally high antioxidant activity .
studies of the same murine model showed that an antioxidant system mediated by nrf2 and nqo1 is activated upon oncogenic ras activation .
however , on the basis of our experimental results it appears that this compensatory response to ras - induced ros production is not sufficient to fully buffer ras - mediated ros accumulation during the process of tumorigenesis .
another example of altered redox homeostasis resulting from an impaired nox4-nrf2 balance has recently been reported in the context of lung fibrosis .
a recent article proposed a novel axis involving activation of p38 through nox1 for ros generation and consequent malignant cellular transformation upon oncogenic k - ras activation in rodent fibroblasts .
another study reported that oncogenic h - ras cooperates with nox1 in rodent fibroblasts or with nox4 in human fibroblasts for establishment of ois .
therefore , it is worth exploring whether the oncogenes that transform both human and murine cells toward tumorigenicity exhibit different preferences for ros source between the two species .
noxzymes are differentially expressed not only among distinct tissues , but also among several different types of cancer ( see fig .
one member of the family is activated as the primary source , whereas the enzymes collaborate in other cancers , for example upregulation of both nox1 and nox4 in colorectal cancer .
understanding which oncogenic stimulus activates each nox enzyme as an initial source for transformation and later proliferation , and how this is influenced by the in vivo microenvironment during tumorigenesis , will undoubtedly help the design of better therapeutic strategies based on ros manipulations .
i am indebted to fabrizio dadda di fagagna for his support throughout the entire project , which is now complemented by a recent publication .
i also thank fabrizio dadda di fagagna , michael bremang , and hans - peter wollscheid for critically reading this manuscript .
 work carried out primarily in the laboratory of fabrizio dadda di fagagna unveils the mitogenic properties of ras - induced reactive oxygen species ( ros ) and their relationship with the dna damage response . 
 combined data from studies of cultured cells , zebrafish models , and clinical material consistently support a role of the ras - rac1-nox4 axis in ros induction , hyperproliferation , and senescence . 
Oncogene-Induced Reactive Oxygen Species and Genome Instability: Hijacking the Good for Hyperproliferation
Oncogene-Induced ROS in Proliferation and Survival: Addiction to the Bad
Oncogene-Induced ROS Manipulations in Cancer: The Enigma
Disclosure of Potential Conflicts of Interest
Acknowledgments