Castration-resistant prostate cancer (CRPC) has specific metabolic characteristics that could make it susceptible to new options for treatment, according to results from cell culture and mouse models of prostate cancer.1
The most common treatment for advanced prostate cancer is to remove androgen to prevent tumor growth, even though the initial effectiveness of this treatment can ultimately lead to CRPC.
“Using an innovative approach to integrate gene expression and metabolomics data, we identified key metabolic pathways that are altered in prostate cancer,” said corresponding author Arun Sreekumar, PhD, professor of Molecular and Cellular Biology, the Alkek Center for Molecular Discovery and the Verna and Marrs McLean department of Biochemistry and Molecular Biology at Baylor College of Medicine, Houston, Texas.
“Of these metabolic pathways, the hexosamine biosynthetic pathway (HBP) showed significant alterations.”
This study, published in Nature Communications, revealed that HBP is significantly less active in CRPC than in androgen-dependent prostate cancers. Reductions in HBP activity are likely to promote growth of tumors.
“When we experimentally knocked down genes involved in HBP in cells similar to CRPC tumor cells, the cells responded with a marked increase in proliferation, both in cell culture and animal experiments,” said Sreekumar.
“When the cells with reduced HBP received UDP-N-acetylglucosamine, a product of this metabolic pathway they lacked, the cells slowed down their growth.”
Researchers administered UDP-N-acetylglucosamine and the clinically used anti-androgen enzalutamide to the CRPC cultured cells. The results were even greater reductions in growth of the disease. These results occurred in spite of the general resistance to anti-androgen therapy that characterizes CRPC.
“This result is particularly noteworthy because our cells were essentially resistant to enzalutamide alone,” said Sreekumar.
These results suggest that studying the features of metabolism of tumors that are resistant to other treatments could result in the discovery of new targets to treat cancer. The identification of HBP as a therapeutic target for CRPC might result in future treatment options for a disease that kills 30 000 people annually in the United States.
1. Kaushik AK, Shojaie A, Panzitt K, et al. Inhibition of the hexosamine biosynthetic pathway promotes castration-resistant prostate cancer [published online May 19, 2016]. Nat Commun. doi:10.1038/ncomms11612.