(left to right, sitting) Yong Zhang, PhD, postdoc; Shengkan "Victor" Jin, PhD, assistant professor, UMDNJ-Robert Wood Johnson Medical School; Haiyan Zhang, graduate student;
(standing) Rebecca Baerga, graduate student; Robert Taylor, graduate student; Joseph Moloughney, graduate student
Autophagy in cancer and aging
According to the American Cancer Society, more than 80 percent of cancers are diagnosed in people age 55 and older. In essence, cancer is a disease of aging. It is not surprising that some processes in cells are involved in both aging and cancer development. Autophagy is one of the most fascinating processes that can potentially rejuvenate an organism and prevent cancer development. That is the focus of our research.
The story started at a coffee break. While working as a postdoctoral fellow at Rockefeller University in the laboritory of Arnie Levine, I was chatting with my friend Zhenyu Yue, a neurobiologist and a postdoc with Dr. Nat Heintz at the time. Inevitably, the conversation switched to science and he complained that a mouse strain he had made failed to exhibit the defect in the nervous system that he had expected. Being a cancer biologist, I naturally led the conversation to cancer. The discussion became more and more interesting. Two cups of coffee later, two enthusiastic young scientists had conceived a comprehensive plan to examine the mysterious mouse strain. It turned out that this strain of mouse, which contains a deletion in a gene called beclin1, has a much higher chance of getting cancer when it is old. In other words, this result demonstrates that the normal function of the beclin1 gene is to prevent tumor development in old age.
Interestingly, the human version of the beclin1 gene is also deleted in sporadic human cancers, tumors affecting only older people. Approximately 50% of sporadic breast cancers, 75% of sporadic ovarian cancers, and 40% of sporadic prostate cancers contain a deletion of the human version of the beclin1 gene. What is even more interesting is that the gene is not related to any known processes that cause cancer. Instead, this gene participates in autophagy, an evolutionarily conserved process that is involved in recycling cytoplasmic components. As shown in Figure 1, autophagy starts with the emergence of a crescent, double membrane structure, which grows and engulfs a portion of cytoplasm, including mitochondria, ribosomes, and proteins. The structure then matures to a closed, double membrane vesicle with a diameter between 0.3 and 0.9 micrometers, which is called an autophagosome or autophagic vacuole. The autophagosome then travels toward the lysosome, a garbage depot and recycling center in the cell. The outer membrane of the autophagosome is then fused with the lysosome membrane, leading to the release of its cargo, which is wrapped by the inner membrane into the lysosome. The cargos are then degraded by the
various enzymes in the lysosome. Basically, it is believed that one function of autophagy is to serve as sanitation workers busily collecting and recycling garbage in the cells.
Strikingly, the same autophagy process has been demonstrated to be important in regulating the life-spans of the flatworm C. elegans, a common and convenient animal model used in the biological laboratory. The laboratory of Beth Levine, MD, at Southwest Medical Center, first cloned the beclin1 gene and independently demonstrated that a mouse strain lacking the beclin1 gene has higher cancer rates, and Leroy Liu, PhD, chair of the Pharmacology Department at UMDNJ-Robert Wood Johnson Medical School (RWJMS), demonstrated that inactivation of autophagy genes shortens the worms’ lives. In the meantime, other scientists, including Zhenyu Yue, PhD, who is now an assistant professor at Mount Sinai School of Medicine in New York and works on the neurobiological aspects of autophagy, found that some aging-related neurodegenerative diseases caused by the abnormal accumulation of protein aggregates in neurons, such as Huntington’s disease, are associated with autophagy reduction. The pharmacological induction of autophagy can help clear the disease-causing aggregates in cells and alleviate the symptoms of these diseases.
An exciting theme then emerged: Autophagy is a critical garbage collecting and recycling process in healthy cells. As we get older, the process slows down or becomes less discriminating. Consequently, haphazard agents are accumulated in cells, which damage various parts of cells and tissues, leading to some aging-related diseases. For example, failure to clear protein aggregates in neurons of the central nervous system causes dementia; failure to clear ROS (reactive oxygen species)-producing mitochondria leads to nuclear DNA mutations and cancer. Collectively, these pathological conditions contribute to, or even define, the process of aging.
|Figure 1: Autophagy, a membrane trafficking process leading to lysosomal degradation, is implicated in cancer, neurodegeneration, and aging.
It is a conceptually simple, intellectually appealing, and experimentally testable hypothesis. Since joining the faculty of the Pharmacology Department of RWJMS in 2003, my laboratory has conducted extensive research around this basic theme. We are working in four interrelated research areas and have been making significant progress. First, we are seeking experimental proof that a defect in autophagy compromises mitochondrial functions, a leading cause of aging. Second, we are determining the direct cause of cancer development as a result of reduced autophagy. Third, we are trying to understand the regulation of autophagy. Fourth, we are exploring the potential of targeting autophagy as a therapeutic adjuvant to cancer therapy. In addition to the Arnold Levine Laboratory, where I was trained as a postdoc, we have made several UMDNJ laboratories our scientific allies along the way, including the labs of Eileen White, William Hait, and Leroy Liu. These various collaborations have helped move the science forward far more quickly.
Three hundred years ago, most people died before the age of 50. Few suffered from cancer, dementia, or type II diabetes. Since the Industrial Revolution, the average lifespan of human beings has increased dramatically. Alas, so has the suffering associated with these aging-related diseases. If autophagy is indeed involved in aging control and preventing those aging-related diseases, understanding autophagy might reveal the secret that prolongs the human lifespan without increasing suffering. Are we looking for the “Holy Grail”? Yes, that is our dream.
Shengkan Victor Jin, PhD, is an assistant professor in the Pharmacology Department at UMDNJ-Robert Wood Johnson Medical School. He obtained his PhD from Cornell University Medical College/Sloan Kettering Cancer Center, followed by postdoctoral training at Rockefeller University. His work has been supported by the UMDNJ Foundation, the New Jersey Commission on Cancer Research, the American Cancer Society, the Department of Defense and the National Institutes of Health.