Itkonen Harri M, Gorad Saurabh S, Duveau Damien Y, Martin Sara E S, Barkovskaya Anna, Bathen Tone F, Moestue Siver A, Mills Ian G
Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Gaustadalleen, Oslo, Norway.
Department of Circulation and Medical Imaging, NTNU, Trondheim, Norway.
Oncotarget. 2016 Mar 15;7(11):12464-76. doi: 10.18632/oncotarget.7039.
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.
代谢网络高度连通且复杂，但单一酶——O-连接的N-乙酰葡糖胺转移酶（OGT）既能感知代谢物的可用性，又能修饰靶蛋白。我们发现，抑制OGT活性会抑制前列腺癌细胞的增殖，导致c-MYC持续缺失，并抑制CDK1的表达，而CDK1表达升高预示着前列腺癌复发（p = 0.00179）。代谢谱分析显示，抑制OGT后葡萄糖消耗和乳酸生成减少。这种糖酵解活性的降低使前列腺癌细胞对氧化磷酸化抑制剂（鱼藤酮和二甲双胍）敏感，而对代表正常前列腺上皮的细胞则无此作用。OGT抑制剂处理后细胞内丙氨酸减少。OGT抑制剂增加了丙氨酸转氨酶（GPT2）的表达和活性，该酶可用临床批准的药物环丝氨酸靶向。同时抑制OGT和GPT2可抑制细胞活力和生长速率，并额外激活细胞死亡反应。这些联合效应主要在前列腺癌细胞中出现，而在源自正常前列腺上皮的细胞系中未出现。用两种针对OGT和GPT2的抑制剂证实了联合治疗的效果。综上所述，我们在此报告了抑制OGT活性后能量代谢的重编程，并确定了前列腺癌细胞特异性的协同致死组合。
