Pitt study finds direct oxidative stress damage shortens telomeres

May 14, 2019

PITTSBURGH, May 14, 2019 - The same sources thought to inflict oxidative stress on cells--pollution, diesel exhaust, smoking and obesity--also are associated with shorter telomeres, the protective tips on the ends of the chromosomal shoelace.

A new study from the University of Pittsburgh, published today in Molecular Cell, provides the first smoking gun evidence that oxidative stress acts directly on telomeres to hasten cellular aging.

"Telomeres consist of hundreds of guanine bases, which are sinks for oxidation," said senior author Patricia Opresko, Ph.D., professor of environmental and occupational health at the Pitt Graduate School of Public Health and UPMC Hillman Cancer Center. "Is it just a coincidence? Or could it be true that oxidizing those guanines in the telomeres is really contributing to shortening?"

To find out for sure, Opresko needed some way to inflict oxidative stress on telomeres and nowhere else.

So, she enlisted the help of Marcel Bruchez, Ph.D., professor of biological sciences and chemistry and director of the Molecular Biosensors and Imaging Center at Carnegie Mellon University. Bruchez developed a method for zeroing in on the telomeres using a special light-activated molecule that latches onto the telomere and delivers localized free radicals--the molecular agent of oxidative stress--on command.

"One of the main challenges to targeting oxidative damage to specific loci in living cells has been achieving precise temporal and dose-control of this damage," Bruchez said. "By combining telomere targeting with our optochemogenetic generation of singlet oxygen, we are able to selectively control when and how hard the oxidative stress is applied specifically at the telomere sites."

The researchers repeatedly exposed cultured cancer cells to this targeted oxidation procedure, mimicking conditions of environmental oxidative stress and inflammation, and, indeed, they saw the telomeres break and shorten with each cell division, despite repair efforts by the telomere lengthening enzyme telomerase.

As the DNA repair machinery tried to fix the broken telomeres, the ends of the chromosomes often fused together, destabilizing the genome and preventing cells from dividing properly.

Whereas telomere shortening spells bad news for healthy cells, Opresko said, the flipside is that targeting telomeres might offer a way to fight cancer. With short enough telomeres, cancer cells would stop dividing.

"If we can understand what causes telomere shortening and how cells compensate for that," Opresko said, "then we'll be in a better position to design intervention strategies that protect telomeres in healthy cells and target telomeres in cancer cells."
-end-
Other authors on this study include Elise Fouquerel, Ph.D., Ryan Barnes, Ph.D., Shikhar Uttam, Ph.D., and Simon Watkins, Ph.D., all of Pitt.

This work was supported by grants from the National Institutes of Health (K99ES027028, R01ES022944, R01CA207342, R01ES02842, R21/R33ES025606 and R01EB017268).

To read this release online or share it, visit http://www.upmc.com/media/news/051419-opresko-ros.

About the University of Pittsburgh Schools of the Health Sciences

The University of Pittsburgh Schools of the Health Sciences include the schools of Medicine, Nursing, Dental Medicine, Pharmacy, Health and Rehabilitation Sciences and the Graduate School of Public Health. The schools serve as the academic partner to the UPMC (University of Pittsburgh Medical Center). Together, their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbeaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care. Since 1998, Pitt and its affiliated university faculty have ranked among the top 10 educational institutions in grant support from the National Institutes of Health. For additional information about the Schools of the Health Sciences, please visit http://www.health.pitt.edu.

About UPMC

A $20 billion health care provider and insurer, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, accountable care. The largest nongovernmental employer in Pennsylvania, UPMC integrates 87,000 employees, 40 hospitals, 700 doctors' offices and outpatient sites, and a 3.5 million-member Insurance Services Division, the largest medical insurer in western Pennsylvania. In the most recent fiscal year, UPMC contributed $1.2 billion in benefits to its communities, including more care to the region's most vulnerable citizens than any other health care institution, and paid $587 million in federal, state and local taxes. Working in close collaboration with the University of Pittsburgh Schools of the Health Sciences, UPMC shares its clinical, managerial and technological skills worldwide through its innovation and commercialization arm, UPMC Enterprises, and through UPMC International. U.S. News & World Report consistently ranks UPMC Presbyterian Shadyside on its annual Honor Roll of America's Best Hospitals. For more information, go to UPMC.com.

http://www.upmc.com/media

Contact: Erin Hare
Office: 412-864-7194
Mobile: 412-738-1097
E-mail: HareE@upmc.edu

Contact: Cyndy Patton
Office: 412-586-9773
Mobile: 412-415-6085
E-mail: PattonC4@upmc.edu

University of Pittsburgh

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.