High levels of cholesterol in the blood are frequently linked with aggressive prostate cancer, and researchers have learned how the cancer cells hijack cholesterol and fuel its growth.
A research team at Duke Cancer Institute revealed that prostate cancer cells often lose their ability to express CYP27A1, a key enzyme in regulating cholesterol levels in the blood. The findings could lead to therapies that target the process, improving the outcomes of prostate cancer patients.
The study, “CYP27A1 loss dysregulates cholesterol homeostasis in prostate cancer,” was published in Cancer Research.
“Prostate cancer cells, as well as some other solid tumors, have been shown to contain higher cholesterol levels than normal cells,” Donald McDonnell, PhD, senior author of the research, said in a press release. “All cells need cholesterol to grow, and too much of it can stimulate uncontrolled growth,” said McDonnell, chairman of the Department of Pharmacology and Cancer Biology at Duke.
“Prostate cancer cells somehow bypass the cellular control switch that regulates the levels of cholesterol, allowing them to accumulate this fat,” he added. “This process has not been well understood. In this study, we show how prostate cancer cells accomplish this.”
Using data from the Cancer Genome Atlas, researchers examined the expression of genes involved in cholesterol metabolism and absorption. They looked for genes that correlated with patients’ conditions, including stage of the disease, whether the prostate cancer had metastasized — or spread — to lymph nodes, and patients’ Gleason score at diagnosis. The Gleason score is a key predictor of long-term prostate cancer treatment results, including survival.
The research team found that CYP27A1 expression was a strong predictor of all three outcomes. Patients with low CYP27A1 levels had the highest Gleason scores, a more aggressive disease, and were more likely to have lymph node metastasis.
CYP27A1 is a key component of the mechanism that regulates cholesterol levels within cells. Without the enzyme, cells cannot tell when they have absorbed enough cholesterol — and just keep absorbing it. Higher cholesterol levels are thought to increase cancer cells’ resistance to chemotherapy, leading to a more aggressive disease.
“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 results from the loss of CYP27A1 expression,” McDonnell said.
Although McDonnell suggests that statins — drugs that lower blood cholesterol levels — could help prostate cancer patients, little is known about statins’ effects on tumor cholesterol levels. His team is working on ways to reduce cholesterol levels in prostate cancer cells, either by ejecting cholesterol, preventing cholesterol production inside the tumor, or by reversing CYP27A1 inhibition.
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