Eileen White, PhD
New Brunswick, N.J. – March 18, 2020 – Research from investigators at Rutgers Cancer Institute of New Jersey shows that a cellular process known as autophagy promotes survival in mouse models by suppressing oxidative stress and a tumor suppressor known as p53. Rutgers Cancer Institute of New Jersey Deputy Director, Chief Scientific Officer, and Associate Director for Basic Research Eileen P. White, PhD, who is a distinguished professor of molecular biology and biochemistry in the School of Arts and Sciences at Rutgers University, is the senior author of the work published March 19 online ahead of print in Genes & Development (DOI: 10.1101/gad.335570.119). She shares more about the research.
Why is this topic important to explore?
Autophagy, a normal cellular process in which intracellular components are recycled leading to sustained cell survival during times of stress. Tumor cells turn on autophagy and use it to promote their own growth, survival, and malignancy. Understanding how autophagy promotes survival in both normal and cancer cells is critically important since inhibiting autophagy is a novel approach to cancer therapy. We need to understand how autophagy works to effectively deploy autophagy inhibition for cancer therapy.
How did the team approach the work and what did you discover?
Using genetically engineered mouse models for autophagy deficiency, we demonstrated that autophagy suppresses activation of the p53 tumor suppressor protein to facilitate development of thymic lymphomas, suggesting that inhibiting autophagy is a new approach to treat lymphomas by promoting p53 activation. We also found that autophagy suppresses p53 activation by Nutlin-3, a novel drug in clinical trials to restore p53 activity and kill cancer cells. These findings also indicate that autophagy is a resistance mechanism to Nutlin-3 therapy. Finally, we found that autophagy suppresses neurodegeneration induced by p53, a potential toxicity of autophagy inhibition therapy.
What are the implications of these findings?
We now know that some of the cancer-promoting activities of autophagy are caused by preventing activation of the p53 tumor suppressor protein, particularly in lymphomas, but also that this protects the brain from neurodegeneration. Thus, autophagy inhibitors should optimally not cross the blood-brain barrier to promote p53 activation selectively in tumors and not in the brain.
The work was supported by funding from the National Institutes of Health (R01 CA130893, R01 CA188096, White).
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