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New research from Rutgers Cancer Institute of New Jersey, Princeton University and other collaborators suggests that inactivation of an essential gene responsible for the cell survival process known as autophagy can suppress the growth of non-small-cell lung cancer tumors and render them more benign. The findings suggest a possible role for autophagy blockers in the treatment of this type of lung cancer, which has a five-year survival rate of only 30 to 50 percent for early-stage disease.
Previous research from the laboratories of the senior authors Eileen P. White, PhD, associate director for basic science at the Cancer Institute of New Jersey and Joshua D. Rabinowitz, MD, PhD, professor of chemistry at Princeton University and Cancer Institute of New Jersey member, revealed that autophagy dependence is prevalent in cancers with Ras mutations. These mutations are activated in aggressive cancers with poor outcomes, such as lung. In this current study, published in the latest online and print versions of Genes & Development (http://www.genesdev.org/cgi/doi/10.1101/gad.219642.113), Drs. White and Rabinowitz and other investigators used mouse models to examine non-small-cell lung cancer tumors driven by activating mutations in the K-Ras cancer gene.
In order to survive times of stress and grow, cancer cells eat themselves. In blocking this self-preservation mechanism of autophagy, cancer cells are stripped of the self-sustaining energy provided through the powerhouse of the cell – the mitochondria. Investigators found in this current study that in the absence of autophagy, or when it is defective, dysfunctional mitochondria accumulate and what once was a malignant tumor becomes a rare, predominantly benign tumor known as an oncocytoma.
The authors also found that the processes necessary for autophagy are influenced by the p53 tumor suppressor gene. When researchers disabled the autophagy gene, the tumor suppressing mechanism of p53 was prematurely activated, thus halting cancer growth and spread. When p53 was removed, investigators determined that Ras-driven tumors are dependent on autophagy to preserve mitochondrial and other functions that help maintain cell viability when changes with the external cell environment are present.
“In finding that autophagy can influence the fate of non-small-cell lung cancer tumors, the possibility now exists to target that mechanism in the treatment of this disease,” noted White, who is also a professor of molecular biology and biochemistry at Rutgers University.
Along with White and Rabinowitz, the author team consists of Jessie Yanxiang Guo and Gizem Karsli-Uzunbas, Rutgers Cancer Institute of New Jersey; Robin Mathew, Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School; Seena C. Aisner, Cancer Institute of New Jersey and Rutgers New Jersey Medical School; Jurre J. Kamphorst, Princeton University; Anne M. Strohecker, Cancer Institute of New Jersey and Robert Wood Johnson Medical School; Guanghua Chen and Sandy Price, Cancer Institute of New Jersey; Wenyun Lu and Xin Teng, Princeton University; Eric Snyder, MIT and Brigham and Women’s Hospital; Urmila Santanam, Cancer Institute of New Jersey; Robert S. DiPaola, Cancer Institute of New Jersey and Robert Wood Johnson Medical School; and Tyler Jacks, MIT.
The study was supported in part by grants from the National Institutes of Health (R37 CA53370 and RO1 CA 130893 to White, RC1 CA 147961 to White and Rabinowitz), the Department of Defense (W81XWH-09-01-0394 to DiPaola and White) and the Val Skinner Foundation.
About Rutgers Cancer Institute of New Jersey
Rutgers Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, the Cancer Institute of New Jersey is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention. Physician-scientists at the Cancer Institute engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support the Cancer Institute of New Jersey, call 732-235-8614 or visit www.cinj.org/giving. Follow us on Facebook at www.facebook.com/TheCINJ.
The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Medical Center, Carol G. Simon Cancer Center at Overlook Medical Center, and Cooper University Hospital. Affiliate Hospitals: CentraState Healthcare System, JFK Medical Center, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), Shore Medical Center, Somerset Medical Center, The University Hospital/Rutgers New Jersey Medical School*, and University Medical Center of Princeton at Plainsboro. *Academic Affiliate