G.M. DeNicola, et al., “Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis,” Nature, 475:106-9, 2011.
The finding suggests that antioxidants, which clear ROS from a cell and are used as a treatment for cancer, may be doing more harm than good—causing complications instead of preventing disease.
“This is an outstanding and really interesting study that further suggests a duplicitous role for ROS in tumorigenesis,” Zachary Schafer, a cancer biologist at the University of Notre Dame, in an email. In 2009, Schafer demonstrated that eliminating ROS helps tumor cells survive outside their extra cellular matrix. Similarly, the new data add to a growing body of literature that challenges the central dogma that antioxidants are always anti-tumorigenic, he said, acting to remove the carcinogenic ROS from tumor cells.
Still, the researchers looked at a transcription factor known to regulate ROS clearance, and that transcription factor has many other important functions that could be affecting the survival of tumor cells, said John Hayes, who studies cancer and antioxidants at the University of Dundee in Scotland and was not involved in the study, in an email. ROS’ tumor-suppressing role has yet to be directly demonstrated.
Previous studies suggest that cancer cells accumulate more ROS than normal cells do, and increasing levels of ROS in cancer cells has been viewed as a bad thing, promoting DNA damage, genetic instability and drug resistance in cells. Yet clinical trials for antioxidants like beta-carotene and vitamin E, which remove ROS and prevent free radical damage, have provided mixed results, some even causing an increase in cancer.
At the Cancer Research UK Cambridge Research Institute, David Tuveson and colleagues noticed that pancreatic cancer cells appeared to be very resistant to stress, and traced this robustness to low levels of ROS in the cells relative to normal cells.
The team investigated by examining a known cellular antioxidant program run by the transcription factor Nrf2, which lowers intracellular ROS, and its suppressor protein, Keap1. They found that three major oncogenes, Kras, Braf and Myc, expressed across a variety of human cancers, increased levels of Nrf2 in tumor cells. This increase in Nrf2 actively lowered intracellular ROS, clearing the cells of free radicals.
“We had expected that oncogenes would cause ROS,” not get rid of them, said Tuveson. So the team double-checked by blocking Nrf2 in mouse models of pancreatic and lung cancer, using genetic and pharmacological means. Consistent with their earlier finding, the loss of Nrf2 led to small, early tumors that didn’t progress. “We found that Nrf2 pathway is important for oncogenes to be fully functional,” said Tuveson.
The surprising result suggests cancer cells can’t grow without Nrf2 suppressing ROS production. It’s possible, therefore, that medicines or vitamins people use in an effort to prevent cancer might actually help keep cancer cells alive. The finding may explain the failed, even harmful clinical trials for antioxidants. “There’s been no understanding of those trials at a molecular level,” said Tuveson. “We now have a potentially new scientific hypothesis to investigate [how ROS and antioxidants] relate to preventing cancer.”
Nrf2, however, also directs the transcription of numerous other pathways in cells, so its influence on ROS may not be the whole story. “Nrf2 regulates a battery of about 100 genes that have other functions,” said Hayes. For example, Nrf2 exerts a robust anti-inflammatory effect, which may be pivotal in allowing tumor cells to survive, he added. Thus, decreased ROS may not be the most important effect of Nrf2’s role in tumor cell survival.
Tuveson’s team plans to investigate that possibility next, exploring which parts of the Nrf2 pathway are the most important in promoting tumors.