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Metabolic Screen Leads to Gene Contributing to Prostate Cancer Survival

NEW YORK (GenomeWeb News) – Metabolic changes hinging around the expression of an enzyme that regulates energy production and antioxidant activity contribute to prostate cancer survival, according to a study appearing online today in the journal Cancer Discovery.

"Cancer metabolism is a new and emerging target that can be exploited as a potential therapeutic," the study's senior author Almut Schulze, with Cancer Research UK's London Research Institute, said in a statement, "and our study identified one of the components for the growth of these cancer cells."

She and her colleagues from the UK and Switzerland used small interfering RNA to systematically knock down 222 metabolism-related genes in three metastatic prostate cancer cell lines, along with a cell line generated from non-malignant prostate tissue. Among the genes targeted were those coding for a range of metabolic enzymes and other proteins contributing to metabolic regulation or metabolite transport.

Though results from the screen hinted at complex collection of metabolic changes in the cancerous cells, one enzyme in particular jumped out at the investigators: a phosphofructokinase isoform coding gene called PFKFB4.

Their subsequent cell line and mouse model experiments indicated that prostate cancer survival is linked to the activity of the glycolytic enzyme encoded by PFKFB4, which helps strike the balance between energy production from glucose and antioxidant formation in the cell.

"[T]his study demonstrates the usefulness of functional screens to identify metabolic weaknesses in cancer cells," Schulze and her colleagues wrote, "and highlights the importance of metabolic regulation to maintain the balance between bioenergetics and antioxidant production for cancer cell survival."

"Targeting this balance may also provide novel strategies for cancer therapy," they added.

Going into the study, Schulze and her team knew that cancer is often marked by jumps in energy production from glucose via a process known as glycolysis and by shifts in the levels of lipids, amino acids, and other metabolites. For example, they explained, androgen hormone signaling in prostate cancer seems to spur on enzymes linked to both glycolysis and fat production. What they were less certain of was whether there might be specific metabolic changes in prostate cancer that might serve as new therapeutic targets.

To look at this in more detail, the researchers focused on 222 metabolic genes in three prostate cancer cell lines — two androgen-independent lines and one androgen dependent line — using a custom siRNA library to systematically knock down each of the genes. For comparison, they did the same siRNA screen in a normal prostate epithelial cell line called RWPE1.

They also analyzed the baseline metabolic behavior of each cell line prior to the screen, examining features such as glucose, glutamine, and oxygen use, lactate secretion, lipid synthesis, metabolite levels, and so on.

All three prostate cancer cell lines showed particularly high glucose dependence, researchers reported. So while their siRNA screen led to some 18 metabolic genes with apparent roles in the survival of at least two of the prostate cancer cell lines tested, the PFKFB4 gene caught their attention.

PFKFB4 was one of only two genes that seemed to influence survival in all three of the prostate cancer lines tested, for example. And experiments in mouse models of prostate cancer indicated that reducing PFKFB4's expression led to less prostate cancer growth and even some tumor regression in the mice.

"Taken together, these results demonstrate that PFKFB4 is required to support prostate cancer cells both in vitro and in vivo," the study's authors wrote.

Through a series of follow-up experiments, they found evidence that PFKFB4's importance in prostate cancer survival reflects its role in glycolysis as well as contributions the enzyme makes to a pathway that keeps reactive oxygen levels in check.

From their findings so far, the team believes that by targeting the gene directly it might be possible to rein in prostate cancer growth while leaving normal tissue nearby unscathed.

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