Abstract
Metabolic networks are highly connected and complex, but a single enzyme, O-GlcNAc transferase (OGT) can sense the availability of metabolites and also modify target proteins. We show that inhibition of OGT activity inhibits the proliferation of prostate cancer cells, leads to sustained loss of c-MYC and suppresses the expression of CDK1, elevated expression of which predicts prostate cancer recurrence (p=0.00179). Metabolic profiling revealed decreased glucose consumption and lactate production after OGT inhibition. This decreased glycolytic activity specifically sensitized prostate cancer cells, but not cells representing normal prostate epithelium, to inhibitors of oxidative phosphorylation (rotenone and metformin). Intra-cellular alanine was depleted upon OGT inhibitor treatment. OGT inhibitor increased the expression and activity of alanine aminotransferase (GPT2), an enzyme that can be targeted with a clinically approved drug, cycloserine. Simultaneous inhibition of OGT and GPT2 inhibited cell viability and growth rate, and additionally activated a cell death response. These combinatorial effects were predominantly seen in prostate cancer cells, but not in a cell-line derived from normal prostate epithelium. Combinatorial treatments were confirmed with two inhibitors against both OGT and GPT2. Taken together, here we report the reprogramming of energy metabolism upon inhibition of OGT activity, and identify synergistically lethal combinations that are prostate cancer cell specific.
Highlights
Prostate cancer is the most common male cancer in Europe and the USA
We recently reported that hexosamine biosynthetic pathway (HBP) enzymes are overexpressed in human prostate cancer patients and that three of the four HBP enzymes are induced by androgen stimulation [2, 17]
First we wanted to identify an inhibitor dose that would modestly inhibit the proliferation of prostate cancer cells but ideally have no or low effects in cells representing normal prostate tissue
Summary
Prostate cancer is the most common male cancer in Europe and the USA. The androgen receptor (AR), a member of the nuclear hormone receptor family, is the major target in the treatment of the disease and its function is the major focus for research. Enhanced AR activity promotes cell survival and proliferation by reprogramming tumour cell metabolism [1,2,3]. AR re-wires the metabolism of the normal prostate tissue, compared to the other differentiated cell and tissue types in the human body. The prostate gland secretes high levels of citrate, which is brought about by AR-regulated zinc accumulation to inhibit cis-aconitase [1]. This leads to www.impactjournals.com/oncotarget decreased TCA cycle activity and ability to produce ATP. In the normal prostate tissue, AR promotes the expression of lipogenic enzymes [4]. AR alters the key energy producing and consuming mechanisms of the cell, and many of these changes are typically associated with proliferating cells
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