Overview

The NRF2 Signaling Pathway

The NRF2 Signaling Pathway

The Zhang laboratory has a number of ongoing research projects focused on understanding Nrf2 regulation and the role of NRF2 in disease. For example, one exciting area of research is screening and developing drugs that target Nrf2 for disease prevention and intervention. Along these lines, the Zhang team has discovered many chemopreventive small-molecules that activate Nrf2 and are effective for mitigating the pathogenesis of a number of diseases. While the current disease models used in the Zhang lab focus on cancer (lung, colon, and skin), diabetes (type I and type II), and neurodegenerative disease (Parkinson’s disease), novel therapies discovered using these models could easily be applied to other disease states. Furthermore, the lab is equipped with state of the art equipment and molecular tools to facilitate the progression of lab projects, including many gene-specific knockout mice or transgenic mice and cell lines.

 

Another key area of interest in the lab involves investigating the dual role of Nrf2 activation in cancer. In 2008, Dr. Zhang presented the unprecedented concept of “the dark side of Nrf2”, in which her group demonstrated that Nrf2 also contributes to chemoresistance, as inhibiting expression of Nrf2 rendered cancer cells more susceptible to chemotherapeutic drugs. Building on this idea, her team identified the first rationally discovered compound, brusatol, to inhibit the Nrf2 pathway. Brusatol was able to overcome intrinsic and acquired chemoresistance in both in vitro and in vivo models, however there were some off target effects. Thus, the Zhang team is currently developing Nrf2 inhibitors with greater specificity, with the hope that someday these compounds will be used therapeutically to overcome cancer resistance to conventional therapies, and thus improve the success of cancer treatment and overall patient survival.

 

Finally, another important area of study in Dr. Zhang’s laboratory is examining the effects of Nrf2 signaling on arsenic toxicity/carcinogenicity. Arsenic is a toxic metalloid whose chronic exposure has been linked to an enhanced risk of disease. Dr. Zhang’s team found that arsenic leads to constitutive Nrf2 activation through autophagy deregulation, which represents a previously unrecognized connection between prolonged Nrf2 activation and arsenic carcinogenicity/diabetogenicity in humans. This work is of great importance, particularly in the environmental toxicology field, and should have a broad impact on diseases caused by arsenic exposure that negatively affect millions of people worldwide.