A new study led by Vanderbilt-Ingram Cancer Center researcher David Gius, M.D., Ph.D., now shows how a deficiency in this aging-associated protein may set the stage for these tumors to develop.
The findings, published in Molecular Cell, provide information that could assist in the screening, prevention and treatment of these common age-related cancers.
While the young are certainly not spared cancer's wrath, cancer is primarily a disease of aging, with the majority of cases occurring in people over 50.
However, the biological processes that underlie this association are not clear.
"The connection between aging and cancer is one of the most established phenomena in cancer research," said Gius, associate professor of Cancer Biology, Pediatrics and Radiation Oncology. "The problem to address this clinically significant question is that this field lacks in vivo models to study this."
In the late-1990s, proteins called "sirtuins" were linked to extended lifespan observed in several species maintained on a calorically restricted diet. These nutrient-sensing sirtuin proteins seemed to defend against aging-related cellular damage.
Sirtuins are present in all living organisms, with humans having seven different sirtuin proteins.
"When (the sirtuins) were discovered, it seemed obvious to conclude that there might be a mechanistic connection between the genes that determine length of survival and cancer," Gius said.
Previously, while at the National Cancer Institute, Gius and colleagues created mice lacking some of these sirtuins. They reported last January in Cancer Cell that when they knocked out Sirt3 — a sirtuin localized in the mitochondria, the cellular "power plants" — the mice developed ER/PR positive breast tumors, the most common type of breast cancer in postmenopausal women.
These tumors also exhibited increased levels of damaging free radicals and "reactive oxygen species" (ROS) — including superoxide, the primary metabolite of oxygen in the mitochondria — which provided an important clue as to how Sirt3 deficiency might permit these tumors to develop.
"The mechanism, at least in part, for why these mice develop receptor positive breast cancer is altered mitochondrial ROS, including superoxide," Gius said.
But how deficiency in a longevity gene led to increased ROS was not clear.
Since superoxide is generally removed from the cell with the help of a detoxifying enzyme called manganese superoxide dismutase (MnSOD), Gius hypothesized that the Sirt3 deficiency may abnormally regulate MnSOD.
In the current study, the researchers show that Sirt3 knockout mice have decreased MnSOD activity despite having normal levels of the protein.
Gius and colleagues determined that the MnSOD in Sirt3 knockout mice was abnormally modified (with a chemical "acetyl" group) at a specific amino acid (lysine 122).
This aberrant modification of MnSOD reduced the enzyme's ability to detoxify superoxide and appeared to explain the increase in ROS in Sirt3 knockout mouse tumors.
"These results suggest that aberrant regulation of MnSOD plays a role in receptor positive breast cancer," said Gius.
Gius and colleagues also developed an antibody that can assess the acetylation status of MnSOD, which he says can potentially be used "to screen breast tissue samples to determine what women are at risk for (receptor positive) cancer or for recurrence because of this dysregulation of MnSOD."
Additionally, agents that target the acetylation of this amino acid on MnSOD may be useful as chemopreventive therapies in women at risk of these cancers and of recurrence, he noted.
The research was supported by grants from the National Cancer Institute and the Department of Defense.
Melissa Marino | EurekAlert!
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences