Researchers have long known that high blood cholesterol and advanced prostate cancer are connected. But until now they couldn’t be sure exactly how the two disorders are linked.
In a study published in Cancer Research, scientists at the Duke Cancer Institute found that cancer cells, by hijacking a cellular process, stockpile cholesterol, which fuels their growth. Identifying this process could result in an improved ability to control cholesterol buildup in tumors, which could lead to increased survival for prostate cancer patients.
“Prostate cancer cells, as well as some other solid tumors, have been shown to contain higher cholesterol levels than normal cells,” said senior author Donald McDonnell, Ph.D., chairman of the Department of Pharmacology and Cancer Biology at Duke. “All cells need cholesterol to grow, and too much of it can stimulate uncontrolled growth.”
“Prostate cancer cells somehow bypass the cellular control switch that regulates the levels of cholesterol allowing them to accumulate this fat,” McDonnell said. “This process has not been well understood. In this study, we show how prostate cancer cells accomplish this.”
The study authors identified genes that play a role in cholesterol regulation in prostate tumors. Specifically, they focused on a gene known as CYP27A1, which helps control the cellular level of cholesterol.
In prostate cancer patients, CYP27A1 gene expression in tumors is considerably reduced, especially in men with aggressive cancers compared to men with more benign disease. When this gene is downregulated, it turns off the sensor that cells need to determine when they have accumulated enough cholesterol. This causes excess lipid levels to build up in tumor cells, giving prostate cancer cells a selective growth advantage.
“It remains to be determined how this regulatory activity can be restored and/or whether it’s possible to mitigate the effects of the increased cholesterol uptake that result from the loss of CYP27A1 expression,” McDonnell said.
According to McDonnell, using cholesterol-lowering statin drugs might help to a certain extent, but their effect may not be enough, since tumors could simply compensate by increasing the regulation of the cholesterol manufacturing process.
The study authors are conducting more research to find ways to cause cells to eject cholesterol, reverse the inhibition of CYP27A1 activity, or introduce substances that interfere with the tumor’s cholesterol production.
Source: Mahmoud A Alfaqih, Erik R Nelson, Wen Liu, Rachid Safi, Jeff S Jasper, Everardo Macias, Joseph Geradts, Laura G Dubois, Will Thompson, Michael R Freeman, Ching-yi Chang, Jen-Tsan Chi, Donald P McDonnell, Stephen J. Freedland. CYP27A1 loss dysregulates cholesterol homeostasis in prostate cancer. Cancer Research, 2017; canres.2738.2016 DOI: 10.1158/0008-5472.CAN-16-2738
