Determining the mechanistic role NFkappaB plays in response to hydrogen peroxide induced cell death

Jessica Ho

Appointment Period: 2007-2010, Grant Years: [23,24,25]

I have studied how oxidative stress modulates the activity of NFkappaB, an event when occurring in the lung ultimately culminates in lung cancer. In addition to oxygen, our lungs are exposed to pollutants and oxidants. These oxidants can lead to the production of reactive oxygen species (ROS), which are chemically reactive oxygen containing species. When ROS overwhelm a cell’s anti-oxidant capabilities, it leads to oxidative stress within the cell.

My project focused on how a particular type of ROS, identified as hydrogen peroxide (H2O2), can activate an important family of cellular proteins, called NFkappaB. NFkappaB is involved in the activation, or repression, of genes involved in inflammation and cell growth, both of which contribute to cancer development and progression. My investigations revealed that H2O2 not only resulted in activation of NFkappaB, but that NFkappaB actually promotes cell death in response to H2O2. This pro-cell death function of NFkappaB is potentially due to the repression of cell survival genes and induction of cell death genes. This result is quite intriguing because NFkappaB is typically associated with cell survival, which is demonstrated by the fact that NFkB is over-activated in many cancers, resulting in use of NFkappaB inhibitors as cancer therapies. Moreover, our observation that NFkappaB can actually promote cell death under H2O2 has important implications for the use of NFkappaB inhibitors in lung cancer therapy.
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Moorthy AK, Savinova OV, Ho JQ, Wang VY, Vu D, Ghosh G. The 20S proteasome processes NF-kappaB1 p105 into p50 in a translation-independent manner. EMBO J. (2006) 25:1945-56. PMID: 16619030; PMCID: PMC1456938.

Ho JQ, Asagiri M, Hoffmann A, Ghosh G. NFkappaB potentiates caspase independent hydrogen peroxide induced cell death. PLoS One. (2011) 6:e16815. PMID: 21347231; PMCID: PMC3039651.