- A molecular mechanism causes kidney cancer to resist drug treatment
- An enzyme called NOX4 is the culprit in kidney cancer evolution
- By reversing energy production back to mitochondria, the free radical production by NOX4 was completely shut off
The molecular mechanism has been identified that causes kidney cancer to resist drug treatment, reveals a new from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and U.S. Department of Veterans Affairs.
The study findings were published in the journal Nature Communications.
‘ATP shifts from within the mitochondria to outside the mitochondria and makes the cancer cells resistant to drug therapy.’
Molecular Mechanism Identified
Nutrients are broken down and processed within the mitochondria in normal cell functioning. This process makes energy available in the form of adenosine triphosphate (ATP).
In 1931, Otto H. Warburg won the Nobel Prize for observing that energy production (ATP) shifts from within the mitochondria to outside the mitochondria and makes the cancer cells resistant to drug therapy.
Since then, scientists have been investigating to identify the critical players involved, so that targeting the pathway can restore cancer cells that are sensitive to drug treatment.
In the Nature Communications
study, research was led by principal investigator Karen Block, Ph.D., who is a longtime associate professor of nephrology at UT Health joined the Department of Veterans Affairs Office of Research and Development in Washington D.C. Last year. To shed light on the processes, she had conducted preclinical experiments and studies in animal xenograft models of human kidney cancer.
Findings of the Study
In a previous study published in 2009, an enzyme called NOX4 was identified by Dr. Block and colleagues within the cell's mitochondria. They revealed that NOX4 is the culprit in kidney cancer evolution.
In this study, scientists focused on identifying the fundamental mechanisms involved. Dr. Block explained that in their first study, NOX4 enzyme generated oxygen radicals, which made the survival of kidney cancer cells undergoing drug treatment complicated.
However, by reversing energy production back to mitochondria, the free radical production by NOX4 was completely shut off, which has killed the cancer cells by exposing to drug treatment.
Ronald Rodriguez, M.D., interim dean of the Joe R. & Teresa Lozano Long School of Medicine and professor of urology at UT Health, who is a co-author on the study explained, "Thirty to 40 percent of patients who have had surgery to remove kidney cancer eventually die because the disease has spread, due to the lack of effective drug therapies and drug resistance."
The research team has revealed that the role of NOX4 in mitochondria is to sense the energetic shift that Warburg described in the 1930s. When ATP production changes, NOX4 turns to become drug resistant and allows the cancer cells to survive, added Dr. Block.
"We think that when this mechanism starts, it develops a NOX4 perpetual loop, allowing cancer to grow and spread. We also think there is the potential that the loop can be reversed. More research needs to be conducted to better understand the mechanism and how we may be able to use drugs to intervene and at which stage," she said.Reference
- Karthigayan Shanmugasundaram, Bijaya K. Nayak, William E. Friedrichs, Dharam Kaushik, Ronald Rodriguez & Karen Block. NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance. Nature Communications (2017). DOI:10.1038/s41467-017-01106-1