SIRT3 Links Oxidative Stress with Aging and Cancer
In a cancer cell, the presence of Myc or Ras mutation along with the lack of SIRT3 alters the metabolism of the cell and increases the levels of reactive oxygen (ROS). This increase of reactive oxygen correlates with an increase in cellular growth rate. Decreasing the reactive oxygen (ROS) through supplementation of SOD inhibits transformation. In a normal cell, SIRT3 possibly acts as a tumor suppressor by regulating ROS.
When cells produce energy, they also form reactive oxygen molecules capable of damaging proteins and DNA. Normally, these molecules are neutralized by a protein called superoxide dismutase, or SOD. However, as a cell ages, oxidative damage accumulates. The increase in oxidative cellular damage as people age may provide a mechanistic connection between aging and carcinogenesis.
The surtuin family of proteins is known to contribute to the cellular lifespan. The removal of these genes from an organism such as a fruit fly greatly reduces the length of its life. One member of the sirtuin family, SIRT3, is expressed in the mitochondria, which is the cellular compartment where energy is produced.
The ability of sirtuin proteins to influence the lifespan of a cell and the connection between aging and cancer made Krish Patel, M.D., working with David Gius, M.D., Ph.D., in CCR's Radiation Oncology Branch and Hyun-Seok Kim, M.D., from the National Institute of Diabetes and Digestive and Kidney Diseases wonder if SIRT3 functions as a tumor suppressor. Drs. Patel and Kim used cell culture techniques and animal models to demonstrate that if SIRT3 is not present in a cell, there is a decrease in the amount of SOD and an increase in reactive oxygen molecules (ROS), which creates an environment that favors the development of cancer.
To begin, the researchers observed the effect of removing SIRT3 from mouse cells. Genetically altered cells that lack SIRT3 showed an increase in reactive oxygen when they were stressed. Removal of SIRT3 also resulted in an increase in mitochondrial DNA damage as the cells aged. When cells were treated to supplement the amount of SOD, which neutralizes reactive oxygen, there was no longer a change in the level of reactive oxygen upon cellular stress.
The researchers also discovered that cells lacking SIRT3 are more amenable to the induction of uncontrolled growth. In a normal cell, mutations in two specific genes—Myc and Ras—cooperate to cause transformation (i.e., acquiring traits of cancer). However, in the absence of SIRT3, mutation of only one or the other gene is sufficient to induce the hallmarks of a cancerous cell. In the presence of Myc or Ras mutation, lack of SIRT3 altered the metabolism of the cell and increased the levels of reactive oxygen (ROS). This increase of reactive oxygen correlated with an increase in cellular growth rate. Decreasing the reactive oxygen (ROS) through supplementation of SOD inhibited transformation.
To determine if SIRT3 is indeed a tumor suppressor, mice were genetically modified to remove the SIRT3 gene. After 24 months, SIRT3-deficient mice developed mammary gland tumors while mice with normal levels of SIRT3 did not. The tumors were estrogen and progesterone receptor positive, which is characteristic of breast cancer in older women. When the expression of SIRT3 was measured in human breast cancer samples, it was found to be lower than in normal breast tissue. Examination of the Oncomine cancer database showed that SIRT3 is also decreased in testicular, glioblastoma multiforme, prostate, head and neck squamous cell, clear cell renal, and hepatocellular cancers.
As people age, they become more likely to develop cancer, but the mechanisms that govern this phenomenon are not fully understood. The identification of SIRT3 as a tumor suppressor suggests a possible link between the proteins that regulate aging and carcinogenesis, and may to be important for several different types of cancer.Summary Posted: Mon, 02/01/2010
Cancer Cell 2010 Jan 19;17(1):41-52 PubMed Link