Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism

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.

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

“…GFAT1 is ubiquitously expressed and GFAT2 is expressed in some tissues like heart, skeletal muscle, lung, and placenta, besides its elevated expression in the central nervous system (DeHaven et al, 2001). Although the relevance of HBP in cancer metabolism has been described in some types of carcinomas such as prostrate (Itkonen et al, 2016), lung (Alisson-Silva et al, 2013), breast (Chanmee et al, 2016), pancreas (Itkonen et al, 2016), and colon (Steenackers et al, 2016), the regulation of this pathway remains largely unknown in tumor cells. Although the relevance of HBP in cancer metabolism has been described in some types of carcinomas such as prostrate (Itkonen et al, 2016), lung (Alisson-Silva et al, 2013), breast (Chanmee et al, 2016), pancreas (Itkonen et al, 2016), and colon (Steenackers et al, 2016), the regulation of this pathway remains largely unknown in tumor cells.…”

O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling

“…Various studies demonstrate a therapeutic window may exist to specifically target OGT and O-GlcNAcylation in cancer cells 39; 40; 80 . A number of novel chemicals have been developed to target OGT and reduce O-GlcNAcylation in mammalian cells.…”

“…In the past 10 years, Walker and colleagues 81; 82 have developed a number of OGT inhibitors aimed at providing insights to the biological and structural function of the enzyme in mammalian cells. Namely, the commercially available small molecule inhibitor ST045849, has been recently shown to stimulate cell death in prostate cancer cells when used in combination with alanine amidotransferase inhibitors 80 .…”

Inhibition of ALDH2 by O-GlcNAcylation contributes to the hyperglycemic exacerbation of myocardial ischemia/reperfusion injury

“…The O -GlcNAcylation of specific proteins could modulate their structure and function and thus influence signaling cascades, antioxidant defenses, et al [9–12]. Up to now, there are numerous reports on O -GlcNAcylation of cytosolic, nuclear and mitochondrial proteins distributed in various tissues [13–15].…”