Abstract
Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial cell line. This approach revealed significant complexity in the metabolic requirements of prostate cancer cells and identified several genes selectively required for their survival. Among these genes was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), an isoform of phosphofructokinase 2 (PFK2). We show that PFKFB4 is required to balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells. Depletion of PFKFB4 inhibited tumor growth in a xenograft model, indicating that it is required under physiologic nutrient levels. PFKFB4 mRNA expression was also found to be greater in metastatic prostate cancer compared with primary tumors. Taken together, these results indicate that PFKFB4 is a potential target for the development of antineoplastic agents. Cancer cells undergo several changes in their metabolism that promote growth and survival. Using an unbiased functional screen, we found that the glycolytic enzyme PFKFB4 is essential for prostate cancer cell survival by maintaining the balance between the use of glucose for energy generation and the synthesis of antioxidants. Targeting PFKFB4 may therefore present new therapeutic opportunities.
Highlights
It is widely accepted that cancer cells alter their metabolic activity to satisfy their increased needs for energy and biosynthetic precursors
Using an unbiased functional screen, we found that the glycolytic enzyme PFKFB4 is essential for prostate cancer cell survival by maintaining the balance between the use of glucose for energy generation and the synthesis of antioxidants
Androgen-independent prostate cancer cell lines, DU145 and PC3, and an androgen-dependent prostate cancer cell line, LNCaP. These were compared with the nontransformed prostate epithelial cell line RWPE1 [17]
Summary
It is widely accepted that cancer cells alter their metabolic activity to satisfy their increased needs for energy and biosynthetic precursors. Many cancers show increased glycolysis, a feature generally known as the Warburg effect, and the importance of biosynthetic processes such as lipid synthesis for cancer cell growth is increasingly recognized [1]. Authors have shown that oncogenic signaling pathways regulate the expression and activity of metabolic enzymes to support macromolecule synthesis in cancer cells, which is required for their rapid proliferation [2]. Enzymes within the core metabolic pathways, including glycolysis, glutaminolysis, and fatty acid biosynthesis, have been shown to be essential for the growth and survival of cancer cells [5,6,7,8,9]. It is evident that metabolic enzymes represent interesting targets for cancer therapy
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