Cancer Cells Resist Dying through Telomerase Regulation

Cancer becomes more common as people get older, but scientists are still searching for answers about why this happens. However, investigators at the Hollings Cancer Center, part of the Medical University of South Carolina, found that human lung cancer cells resist dying by controlling aspects of the aging process.

Findings from the new study – published recently in The Journal of Biological Chemistry, in an article entitled “Balance between Senescence and Apoptosis Is Regulated by Telomere Damage-Induced Association between p16 and Caspase-3” – could help researchers better understand aging and eventually lead to new treatments for cancer.

In the new study, the research team found that cancer cells have specific ways to resist dying the way normal cells do. They protect the tips of their chromosomes, which hold our DNA, from age-related damage. As normal cells age, the advice of their chromosomes, called telomeres, can break down, signaling the cell to die. This is part of the aging process in normal cells. However, cancer cells have developed a way to prevent their telomeres from falling apart, 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.

The Hollings team uncovered how cancer cells escape death in response to telomere damage. Scientists have known that several cancer cells have low protein levels called p16. The investigators found that when telomeres become damaged by age or in response to chemotherapy, p16 is a cellular decision-maker type that helps cells decide to grow older or die.

“Telomeres are like a biological clock for our cells,” explained Besim Ogretmen, Ph.D., chair in lipidomics and drug discovery at the Hollings Cancer Center. “In cancer, this biological clock is broken.”

The researchers found that p16 became most important to cells when their telomeres began to break down. Subsequently, p16 rushes into action and pushes cells toward further aging by inhibiting cell death. To determine the clinical impact of this data, the researchers used a chemical enzyme inhibitor to cause telomere damage in several cancer cells, including lung cancer cells. The inhibitor, ABC294640, acts to prevent cancer cells from protecting their telomeres by inhibiting an enzyme called sphingosine kinase 2. This inhibition was shown to force telomeres to break down.

As a result of this enzyme inhibition, telomeres were damaged, resulting in cancer cell death when p16 levels were low or absent. However, cancer cells with high levels of p16 could escape death and stay biologically inactive, which was a sign of aging.

“We’re excited that there is at least one mechanism that can help us understand how aging is associated with a higher risk of cancer,” noted Dr. Ogretmen. “And then, can we prevent or better treat the aging-related cancers by controlling the protective effects of p16 for cancer cell death?”

Dr. Ogretmen and his colleagues are enthusiastic that the inhibitor in their study might help combat cancer at many levels. The team has already identified the safest dose for patients and is planning a Phase II 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.

“We hope that maybe we can see both delay aging and prevent cancer growth,” Dr. Ogretmen concluded. “That’s the outcome of this.”