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Besim Ogretmen, a researcher at Hollings Cancer Center, is the SmartState Chair in Lipidomics and Drug Discovery at the Medical University of South Carolina. Credit: Brennan Wesley
Scientists at the Hollings Cancer Center of the Medical University of South Carolina have discovered that human lung cancer cells are resisting death by controlling parts of the aging process, according to findings published online on May 10 Journal of biological chemistry. The discovery could help us better understand aging and eventually lead to new treatments for cancer.
Cancer is becoming more common as people get older, but scientists are still looking for answers on why this is happening. At the Hollings Cancer Center, research on the links between aging and cancer is led by Besim Ogretmen, Ph.D., SmartState Chair in Lipidomics and Drug Discovery. The Ogretmen team has discovered that cancer cells have specific ways to resist death like normal cells. They do this by protecting the ends of their chromosomes, which retain our DNA, from age-related damage.
Ogretmen is studying how cancer cells are different from normal cells to understand how cancer develops and spreads in the body. His work is part of a $ 8.9 million grant for a program project to determine how alterations in lipid metabolism affect cancer treatment. The grant helps fund a clinical trial of an anticancer drug aimed at inhibiting cell signaling that helps cancer survive. The drug has been found useful against cancer in research reported in the group's new paper.
As normal cells age, the ends of their chromosomes, called telomeres, can begin to degrade, which is a signal for the cell to die. This seems to be part of the aging process in normal cells. However, cancer cells have developed a way to prevent their telomeres from disintegrating, which helps them to live much longer than normal cells. The long life of cancer cells is part of what allows them to grow and spread throughout the body.
In his new article, the Ogretmen research group discovered a specific way that cancer cells escape death in response to damage caused by telomeres. Scientists have known that different types of cancer cells have low levels of a protein called p16. The Ogretmen group found that when telomeres are damaged by age or in response to chemotherapy, p16 is a type of cellular decision maker, where it helps cells decide to age or simply die .
"Telomeres are like a biological clock for our cells," said Ogretmen. "In cancer, this biological clock is broken."
These laboratory images show the induction of induction of telomere damage (yellow in fused images). Credit: Besim Ogretmen, Ph.D.
The researchers found that p16 became the most important for cells when their telomeres began to break down. When this happened, p16 was precipitated into action and pushed the cells to further aging by inhibiting cell death.
To determine the clinical impact of these data, the researchers used a chemical inhibitor of enzymes to cause damage to telomeres in several types of cancer cells, including lung cancer cells. The inhibitor, ABC294640, acts in a way that prevents cancer cells from protecting their telomeres, by inhibiting an enzyme called sphingosine kinase 2. This inhibition has been shown to force telomeres to decompose.
Due to this inhibition of the enzyme, telomeres were damaged, resulting in death of cancer cells when p16 levels were low or absent. However, cancer cells with high levels of p16 were able to escape death and remained biologically inactive, which was a sign of aging.
"We are delighted that there is at least one mechanism that can help us understand how aging is associated with a higher risk of cancer," Ogretmen said. "And then, can we prevent or better treat age-related cancers by controlling the protective effects of p16 for the death of cancer cells?"
The Ogretmen group is excited that the inhibitor in their study could help fight cancer on many levels. The team has already identified the safest dose to use in patients and is planning a Phase 2 clinical trial using their inhibitor in patients with a type of liver cancer called hepatocellular carcinoma. The multisite trial will include Hollings Cancer Center, Penn State, the University of Maryland, Mayo Clinic and others.
It is particularly important to do this job now, given the predictions predicted by researchers at the National Cancer Institute (NCI) that predict a "silver tsunami" of cancer survivors. The NCI studies show that by 2040, the number of cancer survivors in the United States will increase by nearly 11 million: from 15.5 million in 2016 to 26.1 million in 2040. Much of the cancer survivor population will shift to older populations. It is estimated that by 2040, only 18% of cancer survivors will be between the ages of 50 and 64, and only 8% will be under 50 years of age.
"We hope we can do both: delay aging and prevent cancer growth," said Ogretmen. "It's the end result of this."
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More information:
Shanmugam Panneer Selvam et al, the balance between senescence and apoptosis is regulated by the association induced by telomere damage between p16 and caspase-3, Journal of biological chemistry (2018). DOI: 10.1074 / jbc.RA118.003506
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